Beat Moeckli
Stéphanie Lacotte
Christian Toso- 1Division of Visceral Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- 2Hepatology and Transplantation Laboratory, Division of Visceral Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Introduction
The obesity rate continues to increase and already exceeds 30% in many regions of the world (1). This truly global phenomenon affects women of childbearing age particularly and thus more and more children are born to obese mothers every year (2). Large-scale epidemiological studies have shown that maternal obesity has deleterious effects on offspring health such as increased risk for obesity, liver steatosis and even certain types of cancers (3–5).
The Role of Acsl1 and Aldh2 in Maternal Obesity Related Liver Disease
In a recent study, Sun et al. showed in a murine model of hepatocellular carcinoma that offspring of obese mothers display an increased risk to develop liver cancer (6). Indeed, the authors observed three times as many large tumors in offspring of obese mothers compared to offspring of mothers fed a normal diet. The authors propose a mechanistic link between maternal high-fat diet and the development of liver cancer through the downregulation of two genes, Acyl-CoA synthetase long chain family member 1 (Acsl1) and Aldehyde dehydrogenase family member 2 (Aldh2). Acsl1 codes for an enzyme that is implicated in lipid synthesis and fatty acid degradation through the conversion of free long-chain fatty acids into fatty acyl-CoA esters, the gene is located on 4q35.1 (7). Aldh2 encodes an enzyme of the major oxidative pathway of alcohol metabolism, its genomic location is 12q24.12 (8). Both genes are involved in metabolic processes of the liver. The study suggests that a gradual downregulation of these two genes over several generations is mediated through a specific microRNA, miR-27a-3p.
We recently analyzed the impact of maternal obesity on the gene expression profiles in the offspring (9). We compiled 11 previously published datasets that compared the gene expression in offspring from obese and non-obese parents. All selected studies were performed in mice and assessed the gene expression in the liver of first-generation offspring of different age. We identified a number of genes and pathways that were consistently dysregulated (10–15). In this context, we assessed the gene expression level of Acsl1 and Aldh2 in these datasets. In contrast to the results of Sun et al. we did not see any overall changes in expression for these genes (Figure 1). For a number of datasets Acsl1 is even significantly upregulated. Based on this meta-analysis data we can confidently state that maternal obesity does not affect the expression of Acsl1 and Aldh2 in the first generation of obese offspring.
Figure 1. Meta-analysis of expression of Aldh2 and Acsl1 in offspring of obese mothers in mouse studies. The upper panel represents the meta-analysis of Aldh2 (A) and the lower panel Acsl1 (B). A negative value in the plot indicates a downregulation and a positive value and upregulation of the respective gene.
The results about the increased risk for liver cancer in the offspring of obese mothers described by Sun et al. is convincing and in line with epidemiological data (3, 5). A downregulation of the two proposed genes may well play a role in the experimental setting of the authors. However, we believe it is unlikely that these results are translatable to different experimental contexts or the clinical reality. A regulation of these metabolic genes is unlikely to be solely responsible for the increased risk of liver cancer in offspring of obese mothers.
Discussion
The liver is in close communication with the intestinal tract and exposed to a considerable amount of bacterial products and metabolites. A dysbiosis of the gut microbiome can promote the development of hepatocellular carcinomas (HCC) (16). On the other hand, the altered microbiome of an obese mother is transmitted to the offspring at the time of birth (17). Wankhade et al. have shown that this altered gut microbiome in offspring of obese mothers in turn leads to metabolic changes in the offspring (18). Furthermore, several groups have shown that epigenetic changes that happen during the fetal development are passed on from parents to the offspring and modulate the risk for cancer (19–21). It is likely that these factors also play an important role in the increased risk for HCC in the offspring of obese mothers, besides the regulation of gene expression through specific microRNAs.
The current obesity pandemic will undoubtedly have a long-lasting impact on the health of future generations and given the epidemiological evidence, we will not see the full effect for many decades to come. Sun et al. have recently reported that maternal obesity increases the risk to develop HCC through microRNA mediated downregulation of Acsl1 and Aldh2. In this meta-analysis we showed that the expression of these genes is not affected by maternal obesity in a number of studies. This highlights the importance to study other mechanisms of transmission. More than ever, we need to act and prevent harm to children that are born to obese mothers. We need to fully understand the mechanisms of risk transmission from mother to offspring in order to develop efficient treatments for mothers affected by obesity and their children.
Author Contributions
BM, SL, and CT: conceptualization and writing. BM and SL: formal analysis. SL and CT: supervision, project administration, and funding acquisition. All authors have read and agreed to the published version of the manuscript.
Funding
The Swiss National Science Foundation (Grant Number 182471), the Fondation Francis et Marie-France Minkoff, and the Leenaards Foundation (Grant Number 5489) funded this research.
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.
Acknowledgments
We thank Julien Prados of the Bioinformatics Support Platform for data analysis of the University of Geneva for his help in the curation and analysis of the original dataset.
References
1. Abarca-Gómez L, Abdeen ZA, Hamid ZA, Abu-Rmeileh NM, Acosta-Cazares B, Acuin C, et al. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet. (2017) 390:2627–42. doi: 10.1016/S0140-6736(17)32129-3
2. Wang MC, Freaney PM, Perak AM, Greenland P, Lloyd-Jones DM, Grobman WA, et al. Trends in prepregnancy obesity and association with adverse pregnancy outcomes in the United States, 2013 to 2018. J Am Heart Assoc. (2021) 10:e020717. doi: 10.1161/JAHA.120.020717
3. Hagstrom H, Simon TG, Roelstraete B, Stephansson O, Soderling J, Ludvigsson JF. Maternal obesity increases the risk and severity of NAFLD in offspring. J Hepatol. (2021) 75:1042–8. doi: 10.1016/j.jhep.2021.06.045
4. Stacy SL, Buchanich JM, Ma ZQ, Mair C, Robertson L, Sharma RK, et al. Maternal obesity, birth size, and risk of childhood cancer development. Am J Epidemiol. (2019) 188:1503–11. doi: 10.1093/aje/kwz118
5. Murphy CC, Cirillo PM, Krigbaum NY, Singal AG, Lee M, Zaki T, et al. Maternal obesity, pregnancy weight gain, and birth weight and risk of colorectal cancer. Gut. (2021) 72:1332–9. doi: 10.1136/gutjnl-2021-325001
6. Sun Y, Wang Q, Zhang Y, Geng M, Wei Y, Liu Y, et al. Multigenerational maternal obesity increases the incidence of HCC in offspring via miR-27a-3p. J Hepatol. (2020) 73:603–15. doi: 10.1016/j.jhep.2020.03.050
7. Li T, Li X, Meng H, Chen L, Meng F. ACSL1 affects triglyceride levels through the PPARγ pathway. Int J Med Sci. (2020) 17:720–7. doi: 10.7150/ijms.42248
8. Seo W, Gao Y, He Y, Sun J, Xu H, Feng D, et al. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles. J Hepatol. (2019) 71:1000–11. doi: 10.1016/j.jhep.2019.06.018
9. Moeckli B, Delaune V, Prados J, Tihy M, Peloso A, Oldani G, et al. Impact of maternal obesity on liver disease in the offspring: a comprehensive transcriptomic analysis and confirmation of results in a murine model. Biomedicines. (2022) 10:294. doi: 10.3390/biomedicines10020294
10. Mischke M, Pruis MG, Boekschoten MV, Groen AK, Fitri AR, van de Heijning BJ, et al. Maternal western-style high fat diet induces sex-specific physiological and molecular changes in two-week-old mouse offspring. PLoS ONE. (2013) 8:e78623. doi: 10.1371/journal.pone.0078623
11. Cannon MV, Buchner DA, Hester J, Miller H, Sehayek E, Nadeau JH, et al. Maternal nutrition induces pervasive gene expression changes but no detectable DNA methylation differences in the liver of adult offspring. PLoS ONE. (2014) 9:e90335. doi: 10.1371/journal.pone.0090335
12. Pruis MG, Lendvai A, Bloks VW, Zwier MV, Baller JF, de Bruin A, et al. Maternal western diet primes non-alcoholic fatty liver disease in adult mouse offspring. Acta Physiol. (2014) 210:215–27. doi: 10.1111/apha.12197
13. Kamimae-Lanning AN, Krasnow SM, Goloviznina NA, Zhu X, Roth-Carter QR, Levasseur PR, et al. Maternal high-fat diet and obesity compromise fetal hematopoiesis. Mol Metab. (2015) 4:25–38. doi: 10.1016/j.molmet.2014.11.001
14. Rouschop SH, Karl T, Risch A, van Ewijk PA, Schrauwen-Hinderling VB, Opperhuizen A, et al. Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet. J Lipid Res. (2019) 60:1250–9. doi: 10.1194/jlr.M092593
15. Hedegger K, Philippou-Massier J, Krebs S, Blum H, Kunzelmann S, Förstemann K, et al. Sex-specific programming effects of parental obesity in pre-implantation embryonic development. Int J Obes. (2020) 44:1185–90. doi: 10.1038/s41366-019-0494-x
16. Dapito DH, Mencin A, Gwak G-Y, Pradere J-P, Jang M-K, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. (2012) 21:504–16. doi: 10.1016/j.ccr.2012.02.007
17. Ferretti P, Pasolli E, Tett A, Asnicar F, Gorfer V, Fedi S, et al. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe. (2018) 24:133–45.e5. doi: 10.1016/j.chom.2018.06.005
18. Wankhade UD, Zhong Y, Kang P, Alfaro M, Chintapalli SV, Thakali KM, et al. Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations. PLoS ONE. (2017) 12:e0175675. doi: 10.1371/journal.pone.0175675
19. de Assis S, Warri A, Cruz MI, Laja O, Tian Y, Zhang B, et al. High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring. Nat Commun. (2012) 3:1053. doi: 10.1038/ncomms2058
20. Abbas A, Witte T, Patterson WL, Fahrmann JF, Guo K, Hur J, et al. Epigenetic reprogramming mediated by maternal diet rich in omega-3 fatty acids protects from breast cancer development in F1 offspring. Front Cell Dev Biol. (2021) 9:682593. doi: 10.3389/fcell.2021.682593
Keywords: hepatocellular carcinoma, maternal obesity, origin of disease and health, microbiota, epigenetics
Citation: Moeckli B, Lacotte S and Toso C (2022) The Role of Acsl1 and Aldh2 in the Increased Risk for Liver Cancer in Offspring of Obese Mothers. Front. Med. 9:907028. doi: 10.3389/fmed.2022.907028
Received: 29 March 2022; Accepted: 13 June 2022;
Published: 27 June 2022.
Edited by:
Amanda Sferruzzi-Perri, University of Cambridge, United KingdomReviewed by:
Joel Henrique Ellwanger, Federal University of Rio Grande do Sul, BrazilCopyright © 2022 Moeckli, Lacotte and Toso. 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: Christian Toso, christian.toso@hcuge.ch