Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by over 5% hepatic fat accumulation without secondary causes. The prevalence of NAFLD has escalated in recent years due to shifts in dietary patterns and socioeconomic status, making it the most prevalent chronic liver disease and a significant public health concern globally. Serum uric acid (SUA) serves as the end product of purine metabolism in the body and is intricately linked to metabolic syndrome. Elevated SUA levels have been identified as an independent risk factor for the incidence and progression of NAFLD. This paper reviews the relationship between SUA and NAFLD, the underlying mechanisms of SUA involved in NAFLD, and the potential benefits of SUA-lowering therapy in treating NAFLD. The aim is to raise awareness of SUA management in patients with NAFLD, and to encourage further investigation into pharmacological interventions in this area.
1 Introduction
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by over-accumulation of fat in the liver, defined as steatosis in over 5% of hepatocytes, in the absence of alcohol consumption and other definitive factors causing liver damage (1, 2). The prevalence of NAFLD has been steadily rising due to changes in lifestyle and dietary patterns, making it the most common chronic liver ailment globally (3, 4). The global prevalence of NAFLD is 30.1% (5), with Asian countries reporting a prevalence of 29.6% (6). NAFLD not only has the potential to progress to cirrhosis and liver cancer but is also linked to cardiovascular and cerebrovascular diseases, peripheral vascular diseases, diabetes mellitus, cholelithiasis, and other conditions, as well as an increased risk of various malignant tumors such as colorectal, breast, and pancreatic cancers (7–9). NAFLD is a serious threat to the health of human beings, and it has become a major global concern (10, 11). Given the widespread use of the term NAFLD in existing literature, despite recent proposals to rename it as metabolic-associated fatty liver disease (MAFLD) (12), this review will continue to refer to it as NAFLD.
Uric acid (UA) is the final product of purine compound breakdown in the liver (13), with xanthine oxidase (XO) playing a crucial role in its production by catalyzing the oxidation from hypoxanthine to xanthine and then to UA (14). Abnormalities in UA metabolism are associated with several chronic systemic diseases like hypertension, atherosclerosis, diabetes mellitus, and dyslipidemia (15–17). The relationship between serum uric acid (SUA) levels and NAFLD severity has gained attention in recent years, with SUA being a significant factor independently correlated with the severity of NAFLD independently of other metabolic markers (18). Studies have reported a 21% increase in NAFLD risk for every 1 mg/dL rise in SUA levels (19), with hyperuricemia further elevating the risk of significant liver fibrosis in NAFLD patients (20).
In order to gain a deeper comprehension of the correlation between SUA and NAFLD, this review aims to synthesize current research findings to aid in the management of SUA levels in NAFLD patients.
2 Relationship between SUA and NAFLD
A Meta-analysis has shown a pooled odds ratio of 1.88 in NAFLD patients with higher SUA levels compared to those with lower levels, with SUA levels being associated with NAFLD across various subgroups regardless of study quality, study design, sample size, age, gender, or country (21). Elevated SUA levels are also linked to the severity and progression of NAFLD, with studies indicating a strong correlation between SUA levels and the degree of steatosis, inflammation of the lobules, cirrhosis development, and elevated liver enzymes in NAFLD patients (22, 23). While obesity is a known risk factor for NAFLD (24), increased SUA levels in non-obese individuals significantly heighten the risk of NAFLD, surpassing that in obese patients with normal SUA levels (25). Table 1 provides an overview of relevant studies on the relationship between SUA on NAFLD (18, 22, 25–61).
Table 1
| Size | Types of studies | Country | Main Findings. (Reference) | Author, Year |
|---|---|---|---|---|
| 3,499 | cross-sectional study | China | SUA level demonstrated a positive correlation with the prevalence of NAFLD. A regression equation was developed to predict NAFLD, expressed as follows: The proposed regression formula = 0.032 * WC + 0.303 * BMI + 0.478 * natural logarithm of glutamyl transpeptidase + 1.301 * natural logarithm of triglyceride + 0.002 * SUA - 18.823. When utilizing a cutoff value of 13.3, the model exhibited a sensitivity of 89.2% and a specificity of 78.4% (26). | Ding Y, 2023 |
| 1,343 | cross-sectional study | Korea | SUA levels strongly correlated with fatty liver indices. SUA concentrations in individuals diagnosed with NAFLD and exhibiting abnormal LFT outcomes were notably elevated compared to those without NAFLD and abnormal LFT findings (27). | Park H, 2022 |
| 4,554 | cross-sectional study | China | SUA thresholds were of ≥478 µmol/L and ≥423.5 µmol/L for severe steatosis in male and female MAFLD patients. NAFLD patients with higher SUA levels exhibited greater liver fat accumulation compared to those with lower SUA levels. Even among lean/normal-weight patients with NAFLD, higher SUA levels were associated with an increased likelihood of severe steatosis (28). | He J, 2022 |
| 3,311 | cross-sectional study | China | Increased SUA levels were identified as a facilitating factor for the development of NAFLD after accounting for relevant confounding variables (OR = 2.44). The risk of NAFLD exhibited a linear relationship with rising SUA levels (29). | Wang M, 2022 |
| 27,009 | cohort Study | China | SUA exhibited a positive correlation with the occurrence of NAFLD, particularly among female and non-obese individuals, and was also linked to an increased likelihood of potential advancement of newly diagnosed NAFLD (30). | Tang Y, 2022 |
| 454 | cross-sectional study | Italy | There was a significant correlation between hyperuricaemia and NAFLD (31). | Catanzaro R, 2022 |
| 2,809 | cross-sectional study | China | In patients with type 2 diabetes mellitus, an increased SUA level was identified as a standalone risk factor for the occurrence of NAFLD following accounting for other relevant variables (32). | Hu Y, 2021 |
| 139,170 | cross-sectional study | China | Individuals with MAFLD had a notably higher prevalence of hyperuricemia compared to those without MAFLD (45.0% vs. 16.8%) (33). | Chen YL, 2021 |
| 400 | cross-sectional study | China | The levels of SUA exhibit a significant and autonomous correlation with the occurrence of NAFLD. SUA levels can serve as a valuable indicator for identifying non-obese individuals with type 2 diabetes who are at an elevated risk for developing NAFLD (34). | Cui Y, 2021 |
| 4,323 | cross-sectional study | China | There was a significant positive correlation and dose-response pattern between SUA levels and the incidence of NAFLD in postmenopausal individuals who were not obese. Elevated SUA levels may serve as a potential prognostic indicator for NAFLD in non-obese postmenopausal women (35). | Bao T, 2020 |
| 3,822 | prospective cohort study | China | Elevated SUA levels that exhibit an increasing trend pose a risk factor for NAFLD. This association demonstrates a dose-response relationship that remains consistent across different age groups, genders, and individuals with abdominal obesity (36). | Ma Z, 2020 |
| 2,832 | prospective cohort study | China | NAFLD is directly associated with higher levels of SUA, with elevated SUA concentrations serving as a potential standalone indicator for the development of NAFLD. The established SUA thresholds indicative of NAFLD risk are as follows: ≥288.5 μmol/L for the general population, ≥319.5 μmol/L for males, and ≥287.5 μmol/L for females (37). | Wei F, 2020 |
| 113 | cross-sectional study | Indonesia | Hyperuricemia was identified as a distinct risk factor associated with the development of substantial liver fibrosis (OR = 2.501) (38). | Sandra S, 2019 |
| 100 | cross-sectional study | Pakistan | NAFLD associated with SUA levels (39). | Abbasi S, 2019 |
| 367 | cross-sectional study | Turkey | UA serves as an uncomplicated, non-intrusive, cost-effective, and valuable indicator that can potentially forecast the presence of steatosis in individuals with NAFLD. The identified threshold level for SUA was determined to be 4.75 mg/dl, exhibiting a sensitivity of 45.8% and a specificity of 80.3% (40). | Oral A, 2018 |
| 856 | observational cohort study | China | The likelihood of NAFLD rose in correlation with elevated SUA levels, with SUA level identified as a standalone risk factor for NAFLD, exhibiting a RR value of 1.654 (41). | Bai JX, 2018 |
| 7,569 | cross-sectional study | China | There was a positive correlation between SUA levels and the prevalence of NAFLD, with a slightly stronger association observed in women compared to men. Furthermore, a significant combined effect of SUA levels and serum ALT levels on NAFLD prevalence was noted in all participants, with a slightly greater impact observed in men than in women (42). | Yang H, 2018 |
| 826 | retrospective cohort study | China | In contrast to individuals with normal UA levels, those with hyperuricemia exhibited notably elevated levels of total cholesterol, creatinine, triglycerides, and AST. Furthermore, individuals with hyperuricemia demonstrated a significantly reduced probability of NAFLD remission compared to those with normouricemia (RR = 0.535) (43). | Yang C, 2018 |
| 95,924 | cross-sectional study | China | Increased SUA concentrations were found to be correlated with a heightened likelihood of lean NAFLD. Lean individuals with hyperuricemia exhibited an OR of 1.718 for the presence of NAFLD, following adjustments for additional metabolic disorders. The diagnostic accuracy, as indicated by the AUC, for identifying mild NAFLD using SUA was 0.70, while the AUC for detecting moderate to severe NAFLD based on SUA was 0.78 (44). | Zheng X, 2017 |
| 1,006 | cross-sectional study | China | Elevated SUA levels were linked to a higher risk of NAFLD in both males and females, with OR of 2.645 and 1.962. A notable gender disparity was observed in the association between hyperuricemia and NAFLD, with a statistically significant difference found in males compared to females (45). | Yu XL, 2017 |
| 2,383 | retrospective cohort study | China | The prevalence of NAFLD was found to be higher in individuals with elevated SUA levels compared to those with normal levels (29.0% vs. 12.9%). Hyperuricemia at baseline was significantly linked to an increased risk of developing NAFLD in non-obese individuals. Furthermore, the impact of hyperuricemia on NAFLD risk was more pronounced in females (RR = 2.138) than in males (RR = 1.435) (46). | Yang C, 2017 |
| 4,098 | cross-sectional study | China | Non-obese individuals exhibit a greater susceptibility to NAFLD with elevated SUA levels compared to obese individuals. Furthermore, the advancement of inflammation in NAFLD is linked to elevated SUA levels in non-obese individuals (25). | Liu J, 2017 |
| 841 | prospective cohort study | China | SUA levels exhibited an inverse correlation with the remission of NAFLD. Individuals with elevated SUA concentrations at the outset demonstrated reduced rates of NAFLD remission (47). | Zhou Z, 2016 |
| 158 | cross-sectional study | China | SUA level demonstrated a positive correlation with the extent of steatosis, with a correlation coefficient of 0.177. Patients with hyperuricemia exhibited a higher prevalence of severe lobular inflammation (lobular inflammation score ≥2) compared to those with normal SUA levels (75% vs. 52.7%). Individuals with NAFLD in the hyperuricemic groups displayed a greater incidence of non-alcoholic steatosis (≥5) in comparison to those in the normal SUA groups(48.8% vs. 31.1%). Hyperuricemia was identified as an independent factor associated with advanced lobular inflammation (OR = 2.79) (22). | Huang Q, 2016 |
| 110 | cross-sectional study | Bangladesh | Elevated SUA levels have been found to be closely linked with NAFLD, with this relationship appearing to be influenced by IR in individuals with prediabetes (48). | Hossain IA, 2016 |
| 118 | cross-sectional study | Itady | SUA was identified as a significant independent predictor of non-alcoholic steatohepatitis and its specific histological manifestations, particularly fibrosis (49). | Ballestri S, 2016 |
| 4,305 | cross-sectional study | China | LFC accumulation was found to be linked to a rise in the occurrence of hyperuricemia and elevated SUA levels within a population residing in community settings. An LFC exceeding 10% is correlated with an increased likelihood of developing hyperuricemia (50). | Lin H, 2015 |
| 60,455 | multicenter Study: cross-sectional study and prospective study | China | A gender-specific SUA concentration was found to be linked with NAFLD in a manner independent of other factors. Moreover, the correlation between SUA levels and NAFLD was notably more pronounced in females compared to males (51). | Wu SJ, 2015 |
| 6,967 | cross-sectional study | USA | The incidence of NAFLD was notably greater among individuals with hyperuricemia in comparison to those without (33.8% vs. 14.7%). Those with hyperuricemia exhibited a higher occurrence of elevated liver enzymes in contrast to those without (AST 8.9% vs. 3.0%; ALT 9.6% vs. 4.7%) (52). | Shih MH, 2015 |
| 21,798 | cross-sectional study | China | The risk of NAFLD was notably higher in individuals with elevated SUA levels. Moreover, a significant correlation was observed between SUA levels and prehypertension in terms of the risk of NAFLD (53). | Liang J, 2015 |
| 528 | cross-sectional study | China | Elevated SUA levels, even when falling within the normal range, were positively and independently correlated with the occurrence of hepatic steatosis in postmenopausal Chinese women with a normal BMI (54). | Liu PJ, 2014 |
| 242 | cross-sectional study | Turkey | Hyperuricemia was frequently observed in individuals with NAFLD and was linked to the presence of initial histological manifestations, such as hepatocellular ballooning, in this significant clinical context (55). | Sertoglu E, 2014 |
| 1,440 | epidemiological cohort study | China | In Chinese males, there is a notable correlation between elevated SUA levels and NAFLD. Moreover, within individuals diagnosed with NAFLD, indicators of liver impairment, such as heightened ALT levels in conjunction with a genetic predisposition (specifically the Met196Arg variant in TNFRSF1B (rs1061622)), are linked to elevated SUA concentrations associated with inflammatory processes (56). | Xie Y, 2013 |
| 10,605 | comparative Study | China | The incidence of NAFLD was found to be higher with elevated SUA levels, with a more notable correlation observed in Uyghur individuals compared to Han individuals (OR = 3.279 and 3.230, respectively) (57). | Cai W, 2013 |
| 10,732 | cross-sectional study | USA | An increased serum uric acid (SUA) level was found to be linked with non-alcoholic fatty liver disease (NAFLD) diagnosed through ultrasound in a sample of nondiabetic adults representative of the United States population. Furthermore, a positive correlation was observed between rising uric acid levels and the severity of NAFLD as determined by ultrasonography (18). | Sirota JC, 2013 |
| 9,019 | cross-sectional study | Korean | Elevated SUA levels, even when falling within the normal range, were found to be independently linked to the occurrence of NAFLD (58). | Hwang IC, 2011 |
| 5,741 | cohort study | Korean | Elevated SUA levels were identified as a significant independent risk factor for the development of NAFLD as determined by ultrasonography. After adjusting for relevant variables, the hazard ratio for individuals with hyperuricemia compared to those with normouricemia was 1.29 (59). | Ryu S, 2011 |
| 6,890 | prospective study | China | The rise in SUA levels was a significant independent predictor of heightened risk for developing NAFLD, with the likelihood of NAFLD occurrence rising in correlation with escalating baseline SUA levels (60). | Xu C, 2010 |
| 54,325 | cross-sectional study | China | There was a significant correlation between gout and the risk of NAFLD. Furthermore, a proportional connection was observed between SUA levels and NAFLD risk in individuals both with and without gout (61). | Kuo CF, 2010 |
| 8,925 | cross-sectional study | China | The frequency of NAFLD was notably greater among individuals with hyperuricemia compared to those without hyperuricemia, with rates of 24.75% and 9.54% respectively. Moreover, the prevalence of NAFLD exhibited an upward trend with escalating SUA levels (62). | Li Y, 2009 |
Studies on the relationship between SUA on NAFLD.
NAFLD, nonalcoholic fatty liver disease; SUA, serum uric acid; LFT, liver function test; MAFLD, metabolic-associated fatty liver disease; UA, uric acid; OR, odds ratio; WC, waist circumference; RR, relative risks; BMI, body mass index; AST, aspartate transaminase; AUC, area under the curve; ALT, alanine aminotransferase; AUC, area under curve; LFC, liver fat content; USA, United States of America; IR, insulin resistance; BMI, body mass index. *, multiply.
3 Underlying mechanisms of SUA involved in NAFLD
The pathogenesis of NAFLD has transitioned from the “two-hit” theory to the “multiple hit” hypothesis, which suggests that various factors collectively contribute to the development of NAFLD in genetically susceptible individuals (63, 64). These factors include steatosis, inflammation, oxidative stress (OS), metabolic dysfunction, and insulin resistance (IR) (63, 64). The precise mechanisms through which SUA is involved in NAFLD remain incompletely understood. SUA plays a role in the onset and progression of NAFLD through processes such as OS, inflammatory responses, disturbances in lipid metabolism, and IR, as shown in Figure 1.
Figure 1
3.1 Oxidative stress
OS is an important etiopathogenesis of NAFLD (65). Elevated levels of reactive oxygen species (ROS) under OS can lead to dysfunction in mitochondria and endoplasmic reticulum, as well as reduced antioxidant defenses in liver cells, resulting in inflammation, cell death, and fibrosis during NAFLD progression (66). Hepatocytes exposed to UA has been linked to mitochondrial OS mediated by the translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (67). UA also enhances fat synthesis in hepatocytes by facilitating the transfer of NADPH oxidase subunit 4 to mitochondria, thereby increasing superoxide production (68). Xanthine oxidase (XO), the rate-limiting enzyme enzyme for UA production, generates ROS during catalyzing the oxidative hydroxylation of hypoxanthine and xanthine to produce UA (69). SUA levels can serve as an indicator of XO activity in NAFLD (70). In addition, 70% of fructose in the human body is metabolized by the liver, and fructose-rich diets can exacerbate NAFLD (71). Fructose can exacerbate NAFLD by promoting hepatic fat accumulation through both direct triglyceride (TG) synthesis from fructose metabolism and an uric acid-dependent pathway via mitochondrial OS (72).
3.2 Inflammatory responses
Inflammation is a fundamental component of NAFLD pathophysiology and is present throughout the disease progression (73). UA is a potent inflammatory inducer, capable of upregulating the expression of various inflammation markers in a dose-dependent manner (74). It may also trigger the activation of pro-inflammatory signaling pathways, such as nuclear factor kappa-B, leading to the expression of inflammatory molecules and exacerbating the inflammatory response in hepatocytes (74). The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex involved in recognizing pathogens and molecular patterns, plays a crucial role in obesity, IR, and NAFLD progression (75–77). UA, as an injury-related molecular pattern, stimulates macrophage recruitment (78, 79), which then expresses NLRP3 inflammasome and generate significant quantities of IL-1β (80, 81), leading to chronic inflammation in hepatocytes. UA also exacerbate hepatic inflammation by inducing immune responses through dendritic cells (82).
3.3 Lipid metabolism
The onset of NAFLD is linked to disruptions in lipid metabolism (83). UA plays a role in regulating fatty acid synthase (FASN) through the sterol regulatory element binding protein 1 (SREBP1) signaling pathway, resulting in the accumulation of free fatty acids and compromised energy metabolism in HepG2 cells (84). Additionally, UA triggers the activation of SREBP-1c via endoplasmic reticulum stress, promoting lipid synthesis in hepatocytes, which in turn exacerbates intracellular fat accumulation and lipid degeneration in hepatocytes (85). UA exacerbates lipid metabolism disorders in NAFLD by oxidatively modifying low-density lipoprotein cholesterol and TG synthesis (86). Furthermore, UA facilitates the conversion of fructose to fructose 1-phosphate by activating fructokinase in hepatocytes, leading to fat accumulation through gluconeogenesis (87). Mitochondrial OS induced by UA inhibits aconitase in the Krebs cycle, causing citric acid buildup and stimulating enzymes involved in fatty acid synthesis, ultimately promoting de novo lipogenesis (72). UA significantly up-regulates the expression of miR-149-5p in hepatocytes, and FGF21, a downstream target of miR-149-5p and closely related to lipid metabolism, whose deficiency can lead to hepatic steatosis, so that uric acid aggravated hepatic fat accumulation through the miR-149-5p/FGF21 axis (67). UA upregulates the expression of lipogenic genes in hepatocytes via the ROS/JNK//AP-1 pathway, increasing triglyceride levels in HepG2 cells and leading to the accumulation of intracellular fat in hepatocytes (88).
3.4 Insulin resistance
NAFLD is closely linked to IR, with some considering NAFLD as a hepatic manifestation of IR (89, 90). Obesity is associated with the development of chronic low-grade inflammation, a condition exacerbated by the expansion of adipose tissue (91, 92). The inflammatory characteristics of adipose tissue enhance cytokine production, which in turn contributes to the development of IR (93, 94). In the state of IR, there is an upregulation of lipolysis in adipose tissue, resulting in an increased influx of free fatty acids to the liver (95). Concurrently, hyperinsulinemia stimulates lipogenesis in hepatocytes (96). These metabolic alterations culminate in lipid accumulation within the liver, leading to an increase in intracellular lipid peroxidation products and cytotoxic agents (97). Ultimately, these processes contribute to the onset and progression of NAFLD.The concentration of SUA was found to be independently related with IR (98). UA can inhibit insulin signaling pathways and induce IR by various mechanisms, including activation of the NLRP3 inflammasome and inhibition of IRS1/Akt pathway (72, 99). Elevated SUA levels cause the deposition of urate crystals in pancreatic islets, impairing pancreatic β-cell function and worsening IR (100). Reduced activity of endothelial nitric oxide synthase is also implicated in increased IR in individuals with hyperuricemia (17). Through the aforementioned mechanisms, UA intensifies the level of IR within the body and facilitates the advancement of NAFLD.
4 Potential benefits of SUA-lowering therapy in treating NAFLD
Despite the increasing global prevalence of NAFLD, there remain no FDA-approved pharmacological treatments specifically designed to address this condition, largely due to its intricate pathogenesis and multifactorial nature (101). Currently, lifestyle modifications, including substantial weight loss achieved through a low-calorie diet and increased physical activity, are regarded as the primary interventions for both the prevention and management of NAFLD, as weight reduction is correlated with a decrease in liver fat and may facilitate the reversal of disease progression (102). Bariatric surgery has the potential to decrease hepatic steatosis in obese patients with NAFLD (103). Nevertheless, it is important to note that NAFLD is not considered a valid indication for bariatric surgery (104). In terms of pharmacotherapy, the European and American Association for the Study of the Liver recommends the administration of vitamin E and pioglitazone exclusively for select patients diagnosed with NAFLD (105). More current research hotspots regarding therapeutic agents for NAFLD are mainly focused on drug selection against different metabolic targets (106). Given the significant relationship between SUA levels and NAFLD development, researchers have now recognized that SUA-lowering therapy may have a valuable contribution for improving NAFLD outcomes. XO inhibitors like febuxostat and allopurinol are commonly used to lower SUA levels and have shown promise in improving NAFLD in various studies.
Allopurinol, when administered at a daily dose of 100 mg to patients with hyperuricemia, has been found to lead to a significant reduction in the hepatic controlled attenuation parameter score after a three-month period (107). This medication has demonstrated the ability to decrease TG content in HepG2 cells and in the livers of NAFLD mice by inhibiting XO activity (108, 109). Moreover, allopurinol has shown efficacy in reducing histopathological scores and levels of interleukin-1 (IL-1) and IL-2 immunoexpression in the livers of NAFLD rats (110). By inhibiting NRLP3 inflammasome activation, allopurinol has been observed to mitigate hepatic steatosis and IR by lowering SUA levels (78). In diabetic rats, allopurinol has been found to improve hepatic OS and liver injury through the activation of the Nrf2/p62 pathway (111), as well as to reduce hepatic inflammation and lipid accumulation by decreasing hepatic thioredoxin levels (112). Additionally, allopurinol has been demonstrated to enhance fatty acid beta-oxidation in mouse livers and alleviate high fructose diet-induced hepatic steatosis in diabetic rats by modulating inflammation, lipid metabolism, and endoplasmic reticulum stress pathways (113, 114).
On the other hand, febuxostat has demonstrated a more favorable hepatic safety profile in gout patients with NAFLD (115). Treatment with febuxostat for 24 weeks has resulted in reduced SUA levels, as well as decreased levels of aspartate aminotransferase and alanine aminotransferase in NAFLD patients with hyperuricemia (116). In a nonalcoholic steatohepatitis (NASH) mouse model, febuxostat significantly lowered hepatic XO activity and UA levels, leading to improvements in IR, lipid peroxidation, and the accumulation of classically activated M1-like macrophages in the liver (116). Furthermore, febuxostat has been shown to reduce fat accumulation and ROS in HepG2 cells and NASH mice by downregulating the expression of NLRP3/caspase-1/IL-18/IL-1β and improving IR (117). Administration of febuxostat has also been found to normalize fatty acid oxidation-related genes, collagen deposition, fibrotic changes, lipid peroxidation, and inflammatory cytokine expressions in NASH mice (118).
While both XO inhibitors demonstrated comparable effects in lowering UA levels in the bloodstream, febuxostat exhibited a significant reduction in hepatic UA levels and XO activity in a NASH model in mice, a response not observed with allopurinol (116). This decrease in hepatic UA levels and XO activity was associated with a more pronounced prevention of specific NASH characteristics, including IR, lipid peroxidation, the aggregation of classically activated M1-like macrophages, and hepatic inflammation (116). These findings suggest that febuxostat may possess greater potential for ameliorating NAFLD in patients suffering from hyperuricemia.
5 Limitations
Currently, although advancements have been made in understanding the relationship between SUA levels and NAFLD and proposed a new direction and goal for solving the multifactorial problem of fatty liver, this area of research still faces several limitations. There is a pressing need for more fundamental experimental studies to elucidate the mechanisms through which SUA influences the development of NAFLD, particularly those mechanisms that are directly implicated in the pathogenesis of NAFLD, and the strengths and potential limitations of SUA and its direct association with OS. Observational studies investigating the effects of SUA-lowering therapies on NAFLD have primarily been conducted in preclinical settings or among specific populations with hyperuricemia. This is largely attributable to the insufficient recognition and valuation of SUA-lowering agents in clinical practice for the management of NAFLD, and SUA-lowering therapies on NAFLD is necessitated further investigation into their efficacy and safety, while also focusing on its effects on body weight, glucose and lipid metabolism, and liver tissue pathology. Furthermore, there is a notable absence of research conclusions regarding the use of SUA-lowering therapies for the prevention of NAFLD, as well as the impact of such treatments on NAFLD population without hyperuricemia. To address these gaps, more extensive, long-term, multi-center clinical studies are required to assess the potential benefits of these interventions.
6 Conclusion
In summary, there is a correlation between SUA and NAFLD, with SUA potentially exacerbating NAFLD through various pathways such as OS, inflammatory responses, lipid metabolism disturbances, and IR. Research has explored the potential benefits of SUA-lowering interventions in improving NAFLD. Given the global prevalence of NAFLD and the current limitations in treatment options, identifying novel therapeutic targets for NAFLD is imperative. Targeting XO inhibition as a SUA-lowering therapy may represent a promising avenue for future NAFLD management.
Statements
Author contributions
JF: Writing – original draft. DW: Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by Liaoning Provincial Science and Technology Programme Joint Fund for Doctoral Research Initiation Project, grant number 2023-BSBA-349.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
LvHTaoFPengLChenSRenZChenJet al. In Vitro Probiotic Properties of Bifidobacterium animalis subsp. lactis SF and Its Alleviating Effect on Non-Alcoholic Fatty Liver Disease. Nutrients. (2023) 15:1355. doi: 10.3390/nu15061355
2
TsaiCCChenYJYuHRHuangLTTainYLLinICet al. Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice. Lipids Health Dis. (2020) 19:105. doi: 10.1186/s12944-020-01274-y
3
WangXMaBWenXYouHShengCBuLet al. Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis. Cell Death Discovery. (2022) 8:234. doi: 10.1038/s41420-022-01011-7
4
CongFZhuLDengLXueQWangJ. Correlation between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction in non-obese adults: a cross-sectional study. BMC Gastroenterol. (2023) 23:90. doi: 10.1186/s12876-023-02708-4
5
YounossiZMGolabiPPaikJMHenryAVan DongenCHenryL. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. (2023) 77:1335–47. doi: 10.1097/HEP.0000000000000004
6
LiJZouBYeoYHFengYXieXLeeDHet al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. (2019) 4:389–98. doi: 10.1016/S2468-1253(19)30039-1
7
ChhatwalJDalgicOOChenWSamurSBetheaEDXiaoJet al. Analysis of a simulation model to estimate long-term outcomes in patients with nonalcoholic fatty liver disease. JAMA Netw Open. (2022) 5:e2230426. doi: 10.1001/jamanetworkopen.2022.30426
8
AdamsLAAnsteeQMTilgHTargherG. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. (2017) 66:1138–53. doi: 10.1136/gutjnl-2017-313884
9
LiAAAhmedAKimD. Extrahepatic manifestations of nonalcoholic fatty liver disease. Gut Liver. (2020) 14:168–78. doi: 10.5009/gnl19069
10
ChuXLiLYanWMaH. 4-octyl itaconate prevents free fatty acid-induced lipid metabolism disorder through activating nrf2-AMPK signaling pathway in hepatocytes. Oxid Med Cell Longev. (2022) 2022:5180242. doi: 10.1155/2022/5180242
11
LeeJKimTYangHBaeSH. Prevalence trends of non-alcoholic fatty liver disease among young men in Korea: A Korean military population-based cross-sectional study. Clin Mol Hepatol. (2022) 28:196–206. doi: 10.3350/cmh.2021.0371
12
ZengYHeHAnZ. Advance of serum biomarkers and combined diagnostic panels in nonalcoholic fatty liver disease. Dis Markers. (2022) 2022:1254014. doi: 10.1155/2022/1254014
13
SolimanMMNassanMAAldhahraniAAlthobaitiFMohamedWA. Molecular and histopathological study on the ameliorative impacts of petroselinum crispum and apium graveolens against experimental hyperuricemia. Sci Rep. (2020) 10:9512. doi: 10.1038/s41598-020-66205-4
14
LiXYanZCarlströmMTianJZhangXZhangWet al. Mangiferin ameliorates hyperuricemic nephropathy which is associated with downregulation of AQP2 and increased urinary uric acid excretion. Front Pharmacol. (2020) 11:49. doi: 10.3389/fphar.2020.00049
15
LiCHsiehMCChangSJ. Metabolic syndrome, diabetes, and hyperuricemia. Curr Opin Rheumatol. (2013) 25:210–6. doi: 10.1097/BOR.0b013e32835d951e
16
KatsikiNDimitriadisGDMikhailidisDP. Serum uric acid and diabetes: from pathophysiology to cardiovascular disease. Curr Pharm Des. (2021) 27:1941–51. doi: 10.2174/1381612827666210104124320
17
Sharaf El DinUAASalemMMAbdulazimDO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res. (2017) 8:537–48. doi: 10.1016/j.jare.2016.11.004
18
SirotaJCMcFannKTargherGJohnsonRJChoncholMJalalDI. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism. (2013) 62:392–9. doi: 10.1016/j.metabol.2012.08.013
19
YuanHYuCLiXSunLZhuXZhaoCet al. Serum uric acid levels and risk of metabolic syndrome: A dose-response meta-analysis of prospective studies. J Clin Endocrinol Metab. (2015) 100:4198–207. doi: 10.1210/jc.2015-2527
20
YenPCChouYTLiCHSunZJWuCHChangYFet al. Hyperuricemia Is Associated with Significant Liver Fibrosis in Subjects with Nonalcoholic Fatty Liver Disease, but Not in Subjects without It. J Clin Med. (2022) 11:1445. doi: 10.3390/jcm11051445
21
SunQZhangTManjiLLiuYChangQZhaoYet al. Association between serum uric acid and non-alcoholic fatty liver disease: an updated systematic review and meta-analysis. Clin Epidemiol. (2023) 15:683–93. doi: 10.2147/CLEP.S403314
22
HuangQYuJZhangXLiuSGeY. Association of the serum uric acid level with liver histology in biopsy-proven non-alcoholic fatty liver disease. BioMed Rep. (2016) 5:188–92. doi: 10.3892/br.2016.698
23
AfzaliAWeissNSBoykoEJIoannouGN. Association between serum uric acid level and chronic liver disease in the United States. Hepatology. (2010) 52:578–89. doi: 10.1002/hep.23717
24
PolyzosSAKountourasJMantzorosCS. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism. (2019) 92:82–97. doi: 10.1016/j.metabol.2018.11.014
25
LiuJXuCYingLZangSZhuangZLvHet al. Relationship of serum uric acid level with non-alcoholic fatty liver disease and its inflammation progression in non-obese adults. Hepatol Res. (2017) 47:E104–12. doi: 10.1111/hepr.12734
26
DingYTangZWangMWangMZhangRZhangLet al. Combining serum uric acid and fatty liver index to improve prediction quality of nonalcoholic fatty liver disease. Saudi J Gastroenterol. (2023) 29:191–8. doi: 10.4103/sjg.sjg_484_22
27
ParkHParkKYKimMParkHKHwangHS. Association between serum uric acid level and non-alcoholic fatty liver disease in Koreans. Asian BioMed (Res Rev News). (2022) 16:15–22. doi: 10.2478/abm-2022-0003
28
HeJYeJSunYFengSChenYZhongB. The additive values of the classification of higher serum uric acid levels as a diagnostic criteria for metabolic-associated fatty liver disease. Nutrients. (2022) 14:3587. doi: 10.3390/nu14173587
29
WangMWangMZhangRZhangLDingYTangZet al. A combined association of serum uric acid, alanine aminotransferase and waist circumference with non-alcoholic fatty liver disease: a community-based study. PeerJ. (2022) 10:e13022. doi: 10.7717/peerj.13022
30
TangYXuYLiuPLiuCZhongRYuXet al. No evidence for a causal link between serum uric acid and nonalcoholic fatty liver disease from the dongfeng-tongji cohort study. Oxid Med Cell Longev. (2022) 2022:6687626. doi: 10.1155/2022/6687626
31
CatanzaroRSciutoMHeFSinghBMarottaF. Non-alcoholic fatty liver disease: correlation with hyperuricemia in a European Mediterranean population. Acta Clin Belg. (2022) 77:45–50. doi: 10.1080/17843286.2020.1783907
32
HuYLiQMinRDengYXuYGaoL. The association between serum uric acid and diabetic complications in patients with type 2 diabetes mellitus by gender: a cross-sectional study. PeerJ. (2021) 9:e10691. doi: 10.7717/peerj.10691
33
ChenYLLiHLiSXuZTianSWuJet al. Prevalence of and risk factors for metabolic associated fatty liver disease in an urban population in China: a cross-sectional comparative study. BMC Gastroenterol. (2021) 21:212. doi: 10.1186/s12876-021-01782-w
34
CuiYLiuJShiHHuWSongLZhaoQ. Serum uric acid is positively associated with the prevalence of nonalcoholic fatty liver in non-obese type 2 diabetes patients in a Chinese population. J Diabetes Complications. (2021) 35:107874. doi: 10.1016/j.jdiacomp.2021.107874
35
BaoTYingZGongLDuJJiGLiZet al. Association between serum uric acid and nonalcoholic fatty liver disease in nonobese postmenopausal women: A cross-sectional study. Sci Rep. (2020) 10:10072. doi: 10.1038/s41598-020-66931-9
36
MaZXuCKangXZhangSLiHTaoLet al. Changing trajectories of serum uric acid and risk of non-alcoholic fatty liver disease: a prospective cohort study. J Transl Med. (2020) 18:133. doi: 10.1186/s12967-020-02296-x
37
WeiFLiJChenCZhangKCaoLWangXet al. Higher serum uric acid level predicts non-alcoholic fatty liver disease: A 4-year prospective cohort study. Front Endocrinol (Lausanne). (2020) 11:179. doi: 10.3389/fendo.2020.00179
38
SandraSLesmanaCRAPurnamasariDKurniawanJGaniRA. Hyperuricemia as an independent risk factor for non-alcoholic fatty liver disease (NAFLD) progression evaluated using controlled attenuation parameter-transient elastography: Lesson learnt from tertiary referral center. Diabetes Metab Syndr. (2019) 13:424–8. doi: 10.1016/j.dsx.2018.10.001
39
AbbasiSHaleemNJadoonSFarooqA. Association of non-alcoholic fatty liver disease with serum uric acid. J Ayub Med Coll Abbottabad. (2019) 31:64–6.
40
OralASahinTTurkerFKocakE. Relationship between serum uric acid levels and nonalcoholic fatty liver disease in non-obese patients. Medicina (Kaunas). (2019) 55:600. doi: 10.3390/medicina55090600
41
BaiJXShuRMHuangYPengZ. Correlation between serum uric acid and risk of new-onset nonalcoholic fatty liver disease: a 5-year observational cohort study. Zhonghua Gan Zang Bing Za Zhi. (2018) 26:271–5. doi: 10.3760/cma.j.issn.1007-3418.2018.04.008
42
YangHLiDSongXLiuFWangXMaQet al. Joint associations of serum uric acid and ALT with NAFLD in elderly men and women: a Chinese cross-sectional study. J Transl Med. (2018) 16:285. doi: 10.1186/s12967-018-1657-6
43
YangCYangSFengCZhangCXuWZhangLet al. Associations of hyperuricemia and obesity with remission of nonalcoholic fatty liver disease among Chinese men: A retrospective cohort study. PloS One. (2018) 13:e0192396. doi: 10.1371/journal.pone.0192396
44
ZhengXGongLLuoRChenHPengBRenWet al. Serum uric acid and non-alcoholic fatty liver disease in non-obesity Chinese adults. Lipids Health Dis. (2017) 16:202. doi: 10.1186/s12944-017-0531-5
45
YuXLShuLShenXMZhangXYZhengPF. Gender difference on the relationship between hyperuricemia and nonalcoholic fatty liver disease among Chinese: An observational study. Med (Baltimore). (2017) 96:e8164. doi: 10.1097/MD.0000000000008164
46
YangCYangSXuWZhangJFuWFengC. Association between the hyperuricemia and nonalcoholic fatty liver disease risk in a Chinese population: A retrospective cohort study. PloS One. (2017) 12:e0177249. doi: 10.1371/journal.pone.0177249
47
ZhouZSongKQiuJWangYLiuCZhouHet al. Associations between serum uric acid and the remission of non-alcoholic fatty liver disease in chinese males. PloS One. (2016) 11:e0166072. doi: 10.1371/journal.pone.0166072
48
HossainIAFaruqueMOAkterSBhuiyanFRRahmanMKAliL. Elevated levels of serum uric acid and insulin resistance are associated with nonalcoholic fatty liver disease among prediabetic subjects. Trop Gastroenterol. (2016) 37:101–11.
49
BallestriSNascimbeniFRomagnoliDLonardoA. The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. (2016) 46:1074–87. doi: 10.1111/hepr.12656
50
LinHLiQLiuXMaHXiaMWangDet al. Liver fat content is associated with elevated serum uric acid in the chinese middle-aged and elderly populations: shanghai changfeng study. PloS One. (2015) 10:e0140379. doi: 10.1371/journal.pone.0140379
51
WuSJZhuGQYeBZKongFQZhengZXZouHet al. Association between sex-specific serum uric acid and non-alcoholic fatty liver disease in Chinese adults: a large population-based study. Med (Baltimore). (2015) 94:e802. doi: 10.1097/MD.0000000000000802
52
ShihMHLazoMLiuSHBonekampSHernaezRClarkJM. Association between serum uric acid and nonalcoholic fatty liver disease in the US population. J Formos Med Assoc. (2015) 114:314–20. doi: 10.1016/j.jfma.2012.11.014
53
LiangJPeiYGongYLiuXKDouLJZouCYet al. Serum uric acid and non-alcoholic fatty liver disease in non-hypertensive Chinese adults: the Cardiometabolic Risk in Chinese (CRC) study. Eur Rev Med Pharmacol Sci. (2015) 19:305–11.
54
LiuPJMaFLouHPZhuYNChenY. Relationship between serum uric acid levels and hepatic steatosis in non-obese postmenopausal women. Climacteric. (2014) 17:692–9. doi: 10.3109/13697137.2014.926323
55
SertogluEErcinCNCelebiGGurelHKayadibiHGencHet al. The relationship of serum uric acid with non-alcoholic fatty liver disease. Clin Biochem. (2014) 47:383–8. doi: 10.1016/j.clinbiochem.2014.01.029
56
XieYWangMZhangYZhangSTanAGaoYet al. Serum uric acid and non-alcoholic fatty liver disease in non-diabetic Chinese men. PloS One. (2013) 8:e67152. doi: 10.1371/journal.pone.0067152
57
CaiWWuXZhangBMiaoLSunYPZouYet al. Serum uric acid levels and non-alcoholic fatty liver disease in Uyghur and Han ethnic groups in northwestern China. Arq Bras Endocrinol Metabol. (2013) 57:617–22. doi: 10.1590/s0004-27302013000800006
58
HwangICSuhSYSuhARAhnHY. The relationship between normal serum uric acid and nonalcoholic fatty liver disease. J Korean Med Sci. (2011) 26:386–91. doi: 10.3346/jkms.2011.26.3.386
59
RyuSChangYKimSGChoJGuallarE. Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men. Metabolism. (2011) 60:860–6. doi: 10.1016/j.metabol.2010.08.005
60
XuCYuCXuLMiaoMLiY. High serum uric acid increases the risk for nonalcoholic Fatty liver disease: a prospective observational study. PloS One. (2010) 5:e11578. doi: 10.1371/journal.pone.0011578
61
KuoCFYuKHLuoSFChiuCTKoYSHwangJSet al. Gout and risk of non-alcoholic fatty liver disease. Scand J Rheumatol. (2010) 39:466–71. doi: 10.3109/03009741003742797
62
LiYXuCYuCXuLMiaoM. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. J Hepatol. (2009) 50:1029–34. doi: 10.1016/j.jhep.2008.11.021
63
BuzzettiEPinzaniMTsochatzisEA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. (2016) 65:1038–48. doi: 10.1016/j.metabol.2015.12.012
64
DengALiuFTangXWangYXiePYangQet al. Water extract from artichoke ameliorates high-fat diet-induced non-alcoholic fatty liver disease in rats. BMC Complement Med Ther. (2022) 22:308. doi: 10.1186/s12906-022-03794-9
65
HongTChenYLiXLuY. The role and mechanism of oxidative stress and nuclear receptors in the development of NAFLD. Oxid Med Cell Longev. (2021) 2021:6889533. doi: 10.1155/2021/6889533
66
GonzalezAHuerta-SalgadoCOrozco-AguilarJAguirreFTacchiFSimonFet al. Role of oxidative stress in hepatic and extrahepatic dysfunctions during nonalcoholic fatty liver disease (NAFLD). Oxid Med Cell Longev. (2020) 2020:1617805. doi: 10.1155/2020/1617805
67
XieDZhaoHLuJHeFLiuWYuWet al. High uric acid induces liver fat accumulation via ROS/JNK/AP-1 signaling. Am J Physiol Endocrinol Metab. (2021) 320:E1032–43. doi: 10.1152/ajpendo.00518.2020
68
BrennanPClareKGeorgeJDillonJF. Determining the role for uric acid in non-alcoholic steatohepatitis development and the utility of urate metabolites in diagnosis: An opinion review. World J Gastroenterol. (2020) 26:1683–90. doi: 10.3748/wjg.v26.i15.1683
69
SahaTKumarPSepayNGangulyDTiwariKMukhopadhyayKet al. Multitargeting antibacterial activity of a synthesized mn2+ Complex of curcumin on gram-positive and gram-negative bacterial strains. ACS Omega.. (2020) 5:16342–57. doi: 10.1021/acsomega.9b04079
70
NakatsuYSenoYKushiyamaASakodaHFujishiroMKatasakoAet al. The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model. Am J Physiol Gastrointest Liver Physiol. (2015) 309:G42–51. doi: 10.1152/ajpgi.00443.2014
71
FranceyCCrosJRossetRCrézéCReyVStefanoniNet al. The extra-splanchnic fructose escape after ingestion of a fructose-glucose drink: An exploratory study in healthy humans using a dual fructose isotope method. Clin Nutr ESPEN. (2019) 29:125–32. doi: 10.1016/j.clnesp.2018.11.008
72
LanaspaMASanchez-LozadaLGChoiYJCicerchiCKanbayMRoncal-JimenezCAet al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem. (2012) 287:40732–44. doi: 10.1074/jbc.M112.399899
73
WangHLiYBianYLiXWangYWuKet al. Potential hepatoprotective effects of Cistanche deserticola Y.C. Ma: Integrated phytochemical analysis using UPLC-Q-TOF-MS/MS, target network analysis, and experimental assessment. Front Pharmacol. (2022) 13:1018572. doi: 10.3389/fphar.2022.1018572
74
SpigaRMariniMAMancusoEDi FattaCFuocoAPerticoneFet al. Uric acid is associated with inflammatory biomarkers and induces inflammation via activating the NF-κB signaling pathway in hepG2 cells. Arterioscler Thromb Vasc Biol. (2017) 37:1241–9. doi: 10.1161/ATVBAHA.117.309128
75
StienstraRvan DiepenJATackCJZakiMHvan de VeerdonkFLPereraDet al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U.S.A. (2011) 108:15324–9. doi: 10.1073/pnas.1100255108
76
VandanmagsarBYoumYHRavussinAGalganiJEStadlerKMynattRLet al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. (2011) 17:179–88. doi: 10.1038/nm.2279
77
WuXDongLLinXLiJ. Relevance of the NLRP3 inflammasome in the pathogenesis of chronic liver disease. Front Immunol. (2017) 8:1728. doi: 10.3389/fimmu.2017.01728
78
KonoHChenCJOntiverosFRockKL. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest. (2010) 120:1939–49. doi: 10.1172/JCI40124
79
ShiYEvansJERockKL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. (2003) 425:516–21. doi: 10.1038/nature01991
80
WanXXuCLinYLuCLiDSangJet al. Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism. J Hepatol. (2016) 64:925–32. doi: 10.1016/j.jhep.2015.11.022
81
ZhaoHLuJHeFWangMYanYChenBet al. Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation. Front Immunol. (2022) 13:931087. doi: 10.3389/fimmu.2022.931087
82
RockKLLaiJJKonoH. Innate and adaptive immune responses to cell death. Immunol Rev. (2011) 243:191–205. doi: 10.1111/j.1600-065X.2011.01040.x
83
AoyamaYNaiki-ItoAXiaochenKKomuraMKatoHNagayasuYet al. Lactoferrin prevents hepatic injury and fibrosis via the inhibition of NF-κB signaling in a rat non-alcoholic steatohepatitis model. Nutrients. (2021) 14:42. doi: 10.3390/nu14010042
84
LouBWuHOttHBennewitzKWangCPoschetGet al. Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism. J Transl Med. (2023) 21:199. doi: 10.1186/s12967-023-04050-5
85
ChoiYJShinHSChoiHSParkJWJoIOhESet al. Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest. (2014) 94:1114–25. doi: 10.1038/labinvest.2014.98
86
OzcelikFYiginerO. The relationship between serum uric acid levels and the major risk factors for the development of nonalcoholic fatty liver disease. Liver Int. (2016) 36:768–9. doi: 10.1111/liv.13063
87
LimaWGMartins-SantosMEChavesVE. Uric acid as a modulator of glucose and lipid metabolism. Biochimie. (2015) 116:17–23. doi: 10.1016/j.biochi.2015.06.025
88
ChenSChenDYangHWangXWangJXuC. Uric acid induced hepatocytes lipid accumulation through regulation of miR-149-5p/FGF21 axis. BMC Gastroenterol. (2020) 20:39. doi: 10.1186/s12876-020-01189-z
89
ItabashiFHirataTKogureMNaritaATsuchiyaNNakamuraTet al. Combined associations of liver enzymes and obesity with diabetes mellitus prevalence: the tohoku medical megabank community-based cohort study. J Epidemiol. (2022) 32:221–7. doi: 10.2188/jea.JE20200384
90
ChoiAKimJHChungHKAhnCWChoiHJKimYSet al. The effects of C. lacerata on insulin resistance in type 2 diabetes patients. J Diabetes Res. (2022) 2022:9537741. doi: 10.1155/2022/9537741
91
HotamisligilGSErbayE. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol. (2008) 8:923–34. doi: 10.1038/nri2449
92
OdegaardJIChawlaA. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab. (2008) 4:619–26. doi: 10.1038/ncpendmet0976
93
OlefskyJMGlassCK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. (2010) 72:219–46. doi: 10.1146/annurev-physiol-021909-135846
94
ShoelsonSEHerreroLNaazA. Obesity, inflammation, and insulin resistance. Gastroenterology. (2007) 132:2169–80. doi: 10.1053/j.gastro.2007.03.059
95
NogueiraJPCusiK. Role of insulin resistance in the development of nonalcoholic fatty liver disease in people with type 2 diabetes: from bench to patient care. Diabetes SpectrI. (2024) 37:20–8. doi: 10.2337/dsi23-0013
96
KawanoYCohenDE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol. (2013) 48:434–41. doi: 10.1007/s00535-013-0758-5
97
Sanchez-LozadaLGAndres-HernandoAGarcia-ArroyoFECicerchiCLiNKuwabaraMet al. Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J Biol Chem. (2019) 294:4272–81. doi: 10.1074/jbc.RA118.006158
98
YooTWSungKCShinHSKimBJKimBSKangJHet al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. (2005) 69:928–33. doi: 10.1253/circj.69.928
99
ZhuYHuYHuangTZhangYLiZLuoCet al. High uric acid directly inhibits insulin signalling and induces insulin resistance. Biochem Biophys Res Commun. (2014) 447:707–14. doi: 10.1016/j.bbrc.2014.04.080
100
HanRZhangYJiangX. Relationship between four non-insulin-based indexes of insulin resistance and serum uric acid in patients with type 2 diabetes: A cross-sectional study. Diabetes Metab Syndr Obes. (2022) 15:1461–71. doi: 10.2147/DMSO.S362248
101
SavariFMardSA. Nonalcoholic steatohepatitis: A comprehensive updated review of risk factors, symptoms, and treatment. Heliyon. (2024) 10:e28468. doi: 10.1016/j.heliyon.2024.e28468
102
Vilar-GomezEMartinez-PerezYCalzadilla-BertotLTorres-GonzalezAGra-OramasBGonzalez-FabianLet al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. (2015) 149:367–78.e5; quiz e14-5. doi: 10.1053/j.gastro.2015.04.005
103
TanCHAl-KalifahNSerKHLeeYCChenJCLeeWJ. Long-term effect of bariatric surgery on resolution of nonalcoholic steatohepatitis (NASH): An external validation and application of a clinical NASH score. Surg Obes Relat Dis. (2018) 14:1600–6. doi: 10.1016/j.soard.2018.05.024
104
LaursenTLHagemannCAWeiCKazankovKThomsenKLKnopFKet al. Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects. World J Hepatol. (2019) 11:138–49. doi: 10.4254/wjh.v11.i2.138
105
ChalasaniNYounossiZLavineJECharltonMCusiKRinellaMet al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. (2018) 67:328–57. doi: 10.1002/hep.29367
106
PortincasaPKhalilMMahdiLPerniolaVIdoneVGrazianiAet al. Metabolic dysfunction-associated steatotic liver disease: from pathogenesis to current therapeutic options. Int J Mol Sci. (2024) 25:5640. doi: 10.3390/ijms25115640
107
Al-ShargiAEl KholyAAAdelAHassanyMShaheenSM. Allopurinol versus febuxostat: A new approach for the management of hepatic steatosis in metabolic dysfunction-associated steatotic liver disease. Biomedicines. (2023) 11:3074. doi: 10.3390/biomedicines11113074
108
XuC. Hyperuricemia and nonalcoholic fatty liver disease: from bedside to bench and back. Hepatol Int. (2016) 10:286–93. doi: 10.1007/s12072-015-9682-5
109
SunDQWuSJLiuWYLuQDZhuGQShiKQet al. Serum uric acid: a new therapeutic target for nonalcoholic fatty liver disease. Expert Opin Ther Targets. (2016) 20:375–87. doi: 10.1517/14728222.2016.1096930
110
BarişikVKorkmazHAÇekdemirYETorlakDAktuğHYavaşoğluAet al. The therapeutic effect of allopurinol in fatty liver disease in rats. Acta Endocrinol (Buchar). (2023) 19:155–62. doi: 10.4183/aeb.2023.155
111
ZengFLuoJHanHXieWWangLHanRet al. Allopurinol ameliorates liver injury in type 1 diabetic rats through activating Nrf2. Int J Immunopathol Pharmacol. (2021) 35:20587384211031417. doi: 10.1177/20587384211031417
112
WangWWangCDingXQPanYGuTTWangMXet al. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol. (2013) 169:1352–71. doi: 10.1111/bph.12226
113
LiuJFanYYuHXuTZhangCZhouLet al. Allopurinol protects against cholestatic liver injury in mice not through depletion of uric acid. Toxicol Sci. (2021) 181:295–305. doi: 10.1093/toxsci/kfab034
114
ChoIJOhDHYooJHwangYCAhnKJChungHYet al. Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway. Sci Rep. (2021) 11:9894. doi: 10.1038/s41598-021-88872-7
115
LeeJSWonJKwonOCLeeSSOhJSKimYGet al. Hepatic safety of febuxostat compared with allopurinol in gout patients with fatty liver disease. J Rheumatol. (2019) 46:527–31. doi: 10.3899/jrheum.180761
116
NishikawaTNagataNShimakamiTShirakuraTMatsuiCNiYet al. Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice. Sci Rep. (2020) 10:815. doi: 10.1038/s41598-020-57784-3
117
TangWMuJChenQILiXLiuH. The involvement and mechanism of febuxostat in non-alcoholic fatty liver disease cells. J Biol Regul Homeost Agents. (2018) 32:545–51.
118
KakimotoMFujiiMSatoIHonmaKNakayamaHKiriharaSet al. Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats. J Appl BioMed. (2023) 21:80–90. doi: 10.32725/jab.2023.009
Summary
Keywords
nonalcoholic fatty liver disease, serum uric acid, xanthine oxidase, oxidative stress, NLRP3 inflammasome, lipid metabolism, insulin resistance
Citation
Fan J and Wang D (2024) Serum uric acid and nonalcoholic fatty liver disease. Front. Endocrinol. 15:1455132. doi: 10.3389/fendo.2024.1455132
Received
26 June 2024
Accepted
11 November 2024
Published
28 November 2024
Volume
15 - 2024
Edited by
Roger Gutiérrez-Juárez, National Autonomous University of Mexico, Mexico
Reviewed by
Berwin Singh Swami Vetha, East Carolina University, United States
Jiachen Sun, Dana–Farber Cancer Institute, United States
Yongxiang Li, Baylor College of Medicine, United States
Updates
Copyright
© 2024 Fan and Wang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dongxu Wang, dongxuwangdx@126.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.