Lipids are usually used as energy-storage depots, structural building blocks, and as second messengers in signaling cascades. They accumulate in lipid-storage specialized tissues, such as the adipose one, but are present in almost every cell type due to their importance as energy and carbon skeleton sources, and as hormone precursors. Through β-oxidation, a process in which a series of enzymes oxidize long, medium, or short FAs, cells yield much more ATP than using glucose or glycogen as primary sources. High energy-demanding cells, such as tubular epithelial cells, colonocytes, and myocytes, often use this energy pathway as their main metabolic pathway. Perturbation on lipid metabolism and its enzymes, as well as dietary overload and obesity, lead to cytoplasmic lipid accumulation and, consequently, lipotoxicity (Kang et al., 2015; Adeva-Andany et al., 2019; Cockcroft, 2021).

In general, lipids are a very diverse group of molecules, but with one characteristic in common: insolubility in water. Storage lipids are often fats, and their derivatives are FAs. They are composed of hydrocarbons, with a carbon skeleton, and may be branched or not. Unsaturation is characterized by a double bond between two carbon atoms, in a cis or trans configuration. Oxidation of FAs is a very exergonic reaction, thus producing a lot of energy that is converted into ATP in the mitochondrion (Cockcroft, 2021).

FAs uptake is mediated by three main transporters, CD36 or fatty acid translocase (FAT), fatty acid binding protein (FABP), and fatty acid transport protein (FATP). After the entrance into the cell cytoplasm, very long- and long-chain FAs are initially α- and β-oxidized in peroxisomes, and their metabolites, together with medium-chain FAs enter mitochondria through the L-carnitine shuttle system to start a new round of β-oxidation. At the end, acetyl-CoA is generated and enters the TCA cycle (Mannaerts et al., 2000; Luiken et al., 2002; Jansen and Wanders, 2006; Storch and McDermott, 2009; Schwenk et al., 2010; Anderson and Stahl, 2013; Melton et al., 2013).

Phospholipids are the major components of biological membranes and are composed of two hydrophobic fatty acyl chains and one hydrophilic head group. The fatty acyl chains are responsible for biological and physical properties affecting all biological processes that occur in the inner and outer membrane leaflets. Alterations in the fatty acyl chains are orchestrated by reacylation and deacylation, known as the Land’s cycle (Van Meer et al., 2008; Wang and Tontonoz, 2019; Cockcroft, 2021). Perturbance of phospholipid content in the cell membrane may be involved in the pathogenesis of some diseases, including bacterial infections.

Intracellular pathogens have well-defined mechanisms to exploit the host’s cell lipid metabolism and use those molecules as an energy source for their metabolic processes. In extracellular pathogens, lipid metabolism impairment and metabolism exploitation are still not completely elucidated (Walpole et al., 2018; Libbing et al., 2019).

Besides lipids’ roles in disease pathogenesis, there is a crescent body of information outlining lipid droplets (LDs) as a hub that integrates metabolic and inflammatory responses to face infections (Monson et al., 2021b). In viral infections, LDs are used as the site of viral replication, since it is partially protected against the machinery of pathogen killing. They also use the lipid content from LDs to build up their capsids (Samsa et al., 2009; van der Meer-Janssen et al., 2010; Farías et al., 2022). Furthermore, foamy macrophages, a hallmark of tuberculous lesions, are generated after Mycobacterium species induction of LDs formation (Agarwal et al., 2021).

This review aims to describe lipid metabolism and exploitation of lipids, lipid metabolism, and cell membrane phospholipids by pathogens, as well as their consequences to cells and organisms.

Lipids are molecules composed of a hydrocarbon chain, branched or not, with a carboxyl-terminal group. As mentioned above, unsaturated FAs have a double bond between two carbons in the cis or trans position. Saturated FAs have linear chains with no double bonds along them, that may be as small as those with two carbons (acetic acid) or as large as those with 26 carbons (cerotate) (Adeva-Andany et al., 2019).

Lipid metabolism is a very complex process that involves both anabolic and catabolic reactions. The process starts with FA degradation and absorption by the gastrointestinal tract and the interaction of lipids with the gut microbiome. As this particular subject is beyond the scope of this review, the interested reader may search for additional information, well provided by Schoeler and Caesar (2019), who extensively discuss this aspect of lipid metabolism. Here we will focus on intracellular lipid metabolism and its importance for maintenance of the cellular functioning.

CD36, also known as fatty acid translocase, is a receptor of the scavenger receptor family that mediates the uptake of FAs from the extra- to the intracellular milieu (Luiken et al., 2002; Pepino et al., 2014; Hou et al., 2015; Hua et al., 2015; Yang et al., 2017; Jay and Hamilton, 2018). It is an integral membrane protein, highly glycosylated, and present in erythrocytes, platelets, immune cells, adipocytes, enterocytes, and epithelial cells (Pepino et al., 2014). Although it has a well-described function as a FA transporter, CD36 is also involved in the recognition of other molecules, such as thrombospondin, collagen, Plasmodium-infected erythrocytes, and oxidized-LDL (Nicholson et al., 2001; Silverstein and Febbraio, 2010; Jay and Hamilton, 2018; Maréchal et al., 2018; Pombinho et al., 2018).

It is known that CD36 production is augmented during acute and chronic kidney diseases, which is associated with epithelial-to-mesenchymal transition (EMT) and inflammation in animal and cellular models of kidney injury (Hou et al., 2015; Hua et al., 2015; Yang et al., 2017). Endothelial cells are also prone to undergo endothelial-to-mesenchymal transition after infection or disturbance of cell functioning. In primary endothelial cells infected by Leptospira interrogans CD36 is overexpressed in the cell membrane, as evidenced by immunofluorescence microscopy (Sato and Coburn, 2017).

Treatment of bovine mammary epithelial cells with palmitate leads to CD36 gene overexpression, in a dose-dependent manner. Cells treated with as much as 600 µM of palmitate have CD36 gene expression augmented at almost 40-fold compared to those without any treatment, which highlights the importance of this receptor in lipid uptake, and how lipid intake may influence its concentration in the cell membrane (Qi et al., 2014).

Other receptors are involved in lipid uptake to the cytoplasm, such as fatty acid transporter proteins 1 to 6 (FATP 1-6) and fatty acids binding proteins (FABPs) (Melton et al., 2013). FATPs are also integral membranes with different roles, according to each type. Collectively they are described as membrane-bound proteins that act in the uptake of long-chain FAs and in the activation of FAs, as the first step of β-oxidation, i.e., acylation, of very long-chain FAs (DiRusso et al., 2005; Anderson and Stahl, 2013; Melton et al., 2013).

FABPs have a high affinity to long-chain FAs and bind both saturated and unsaturated FAs (Storch and McDermott, 2009). There are multiple FABPs functioning similarly, and the affinity to a given FA increases as hydrophobicity rises. There are 9 different FABP types described to date, known as FABP 1-9 (Ono, 2005; Li et al., 2020). Different isoforms are named after the main organ where they were described (Furuhashi, 2019). These proteins, also characterized as chaperones, exert functions in FA transport and in intracellular communication (Gorbenko et al., 2010).

Besides being internalized by receptors, endocytosis is also used as a means of transporting lipids into the cell cytoplasm. The most well-studied forms of general endocytosis are the ones mediated by clathrin and caveolin (Johannes et al., 2016; Kaksonen and Roux, 2018; Kostarnoy et al., 2022; Abdulova et al., 2023; Liu et al., 2023; Tang et al., 2023; Yu and Yoshimura, 2023). More recently, a new mechanism of lipid transport and uptake, named Mincle-mediated endocytosis (MiMe) was described. The Mincle receptor was first reported as a pattern recognition receptor (PRR) and plays a role in triggering inflammatory responses after the recognition of fungal and bacterial lipids. However, it also mediates lipid uptake, as the knockout of Mincle leads to a pronounced decrease in lipid internalization by brain vessel endothelial cells.

Free FAs, or albumin-bound FAs are present in the bloodstream and enter the cells by their transporters, as described above. After their entry into the cytoplasm, FAs are activated by the enzyme fatty acyl CoA synthetase that catalyzes the binding of an Acyl-CoA to each acetyl moiety. Very long-chain FAs must be shortened by peroxisomal α-oxidation before entering mitochondria (Adeva-Andany et al., 2019).

Carnitine palmitoyl transferase 1 (CPT1) then catalyzes the transfer of acylcarnitine to the inner mitochondrial membrane. This process occurs with the acyl groups being transferred from Coenzyme A (CoA) to L-carnitine, generating the acylcarnitine esters that are allowed to pass through the mitochondrial outer membrane. Carnitine acyl-carnitine translocase (CACT) transports the acyl-carnitine esters into the mitochondrial matrix in exchange for a free carnitine. Finally, Carnitine palmitoyl transferase 2 (CPT2) catalyzes fatty acyl-CoA esters import into the mitochondria, transferring the acyl groups from the acyl-carnitine esters, generating acyl-CoA esters (Adeva-Andany et al., 2019).

In the mitochondrial matrix, Acyl-CoA is cleaved from FA-Acyl-CoA by β-oxidation and enters the TCA cycle to generate ATP (Berndt et al., 2019; Gewin, 2021). The whole β-oxidation process is catalyzed by only four different enzymes, e.g., Acyl-CoA dehydrogenase, Enoyl-CoA hydratase, 3-L-hydroxyacyl-CoA dehydrogenase, and β-ketothiolase. After the four rounds, there is generation of an acetyl-CoA that enters the TCA pathway, and an Acyl-CoA ester, with two carbons less. These iterative rounds keep happening until total Acyl-CoA esters are consumed (Adeva-Andany et al., 2019).

Conversely, acetyl-CoAs that are produced in the mitochondria and are not used in TCA are exported to the cytosol, and back to the ER, where they are used in lipogenesis, contributing to the biosynthesis of neutral lipids and phospholipids (Wältermann et al., 2007; Turchetto-Zolet et al., 2011; Hsu et al., 2023) De novo lipid synthesis or lipid biogenesis is governed by the mTORC1 signaling pathway (Düvel et al., 2010; Li et al., 2010; Peterson et al., 2011; Owen et al., 2012; Han et al., 2015; Lee et al., 2017), which is responsible for lipogenic enzyme production by SREBP 1 and 2 induction or reduction of their inhibitors (Düvel et al., 2010; Li et al., 2010; Peterson et al., 2011; Owen et al., 2012; Han et al., 2015). Another important role of the mTORC pathway is mediated by SRKP2 that induces more efficient mRNA splicing of lipogenic enzymes, thus enhancing de novo lipid synthesis (Lee et al., 2017).

In this way, lipids are produced after the generation of Acetyl-CoA, in the TCA cycle, from either citrate or acetate by ATP citrate lyase (ACLY) or acyl-CoA synthetase short-chain (ACSS). Fatty acid synthesis then takes place by using Acetyl-CoA and Malonyl-CoA, catalyzed by Fatty Acid Synthetase. The addition of more acetyl-CoA will lead to the formation of a palmitate molecule which is then used to generate longer FAs by elongation processes, unsaturated FAs catalyzed by stearoyl-CoA desnaturase 1 (SCD1), and finally phospholipids and signaling lipids (Lee et al., 2017). Although produced in the mitochondria, the cytosolic acetyl-CoA pool is used by lipogenic enzymes for FA biosynthesis. In vitro, cells under glucose restriction use more acetyl-L-carnitine to generate acetyl-CoA and consequently, fatty acids. Therefore, L-carnitine not only participates in the L-carnitine shuttle but also represents a carbon source to cells under physiological or hypoglycemic environment (Hsu et al., 2023).

Other important mechanism involved in cell homeostasis and pathogen response is macroautophagy, or simply autophagy. During this process, cells engulf and destroy organelles to maintain proper functioning. The phagophore, a double-membrane vacuole, is responsible for engulfing the organelles and fusing them with lysosomes where hydrolysis occurs. The formation of the phagophore is mediated by membrane donation from healthy organelles, but also by de novo synthesis of FAs in the ER, catalyzed by long-chain Acyl-CoA synthetase (ACS), in particular by the enzyme Faa1 (Schütter et al., 2020).

Triacylglycerol, a glycerolipid, is used as storage and is composed of three FAs attached to the three hydroxyl groups of the glycerol backbone (Cockcroft, 2021). Cell membranes are composed of three main lipids: glycerophospholipids, sphingolipids, and sterols, such as cholesterol. Mammalian cells synthesize and yield phospholipids that are not present in prokaryotes, such as phosphatidylserine, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidylglycerol. The percentage of each molecule varies according to the cell type and environment (Wang and Tontonoz, 2019; Cockcroft, 2021).

Neutral lipids are synthesized in the ER mainly as triacylglycerol and are stored in LDs. The most important enzymes, that are rate limiting in the synthesis of triacylglycerol, are acyl-CoA diacylglycerol acyltransferase (DGAT) 1 and 2, responsible for catalyzing the acylation of sn-1,2-diacylglycerol, using acetyl-CoA as a substrate. Evolutionary studies have shown that these enzymes are conserved in all eukaryotes, despite molecular and genetic differences (Turchetto-Zolet et al., 2011). Inhibition of DGAT 1 and 2 leads to decreased LD formation, and to impaired viral replication and bacterial survival during infections (Monson et al., 2021a; Yuan et al., 2021; Kiarely Souza et al., 2022; Dias et al., 2023).

Membrane phospholipid synthesis occurs in the ER. Phosphatidic acid (PA) is used as the precursor of most of the other phospholipids in the host’s cells. A two-round acylation of glycerol-3-phosphate is mediated by the enzymes Glycerol-3-Phosphate Acyltransferase (GPAT) and Lyso-PA Acyltransferase (LPAAT), with PA as an end product. From PA, other phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine are produced. Phosphatidylglycerol and cardiolipin are synthesized in the mitochondria. After their synthesis, phospholipids are addressed to the cytoplasmic and other membranes in the cell and are integrated into them (Van Meer et al., 2008; Cockcroft, 2021).

LDs are important organelles for cellular functioning and are constituted by high hydrophobic neutral FAs, within an aqueous environment. LDs are present in almost every cell in the organism and are responsible for FAs and specific protein storage, besides taking part in other complex processes, such as viral replication (Walther and Farese, 2012).

A family of proteins named perilipin (PLINs) is involved in lipid uptake, coating, and addressing LDs inside cells (Frank et al., 2015; Najt et al., 2022). Perilipin 1 was the first perilipin described (Greenberg et al., 1991) and after its discovery, the study of LDs, their lipidomic and proteomics, and the role of LDs in health and disease have increased dramatically, expanding the LD biology field (Kobayashi et al., 2008; Kuerschner et al., 2008; García-Arcos et al., 2010; Turchetto-Zolet et al., 2011; Hsieh et al., 2012; Lin et al., 2014; Markgraf et al., 2014; Kamili et al., 2015; Li et al., 2015; Viktorova et al., 2018; Freyre et al., 2019; Guyard et al., 2022; Kim et al., 2022; Oluwadare et al., 2022).

Assembly of LDs in the cytoplasm is thought to occur in very close proximity to the ER, but the exact mechanism by which those organelles are formed is still not completely understood. It has been shown that ER, mitochondria, and LDs are in close contact during LD formation and that this contact is mediated by two proteins called oxysterol binding protein (OSBP)-related protein (ORP) 5 and ORP8 (Guyard et al., 2022). Besides those, PLIN2 is involved in FA uptake and in addressing it in the forming LD (Hsieh et al., 2012; Najt et al., 2022). Other protein that may be involved in the inflammatory response and LD formation is the cell death-inducing DFF45-like effector b (Cideb). Mice lacking this protein are more prone to developing severe DSS-induced colitis and even more severe DSS-induced colitis if they undergo a high-fat diet (Sun et al., 2017). After the formation of a LD, enlargement is achieved by the fusion of multiple droplets. Besides the phospholipid monolayer, that separates LDs from the aqueous environment of the cytoplasm, there are also specific proteins attached to or in close relation with the LD’s phospholipid monolayer (Walther and Farese, 2012).

Usage (lipolysis) or storage (lipogenesis) of lipid content from LDs are very strictly regulated. Insulin and glucagon participate in this regulation, as they are major regulators of metabolism (Walther and Farese, 2012). Within the cell, the mechanism of new LD formation is still under debate, but the production of triacylglycerols and sterol ester by enzymes localized in the ER and the budding of the nascent LD from the ER membrane is one of the proposed mechanisms. Otherwise, usage of lipid content from LDs is mediated by lipases, such as the Adipose Triacylglycerol Lipase (ATGL) that converts triacylglycerol to diglyceride, and the Hormone-sensitive Lipase (HSL) that breaks diglyceride into monoglyceride (Walther and Farese, 2012; Monson et al., 2021b). The involvement of other cellular mechanisms in lipid metabolism has been described, though yet not fully understood (Singh et al., 2009; Yan et al., 2018; Jarc and Petan, 2019).

Autophagy seems to control LD digestion and lipolysis. Inhibition of autophagy in hepatocytes by knocking down the Atg5 gene leads to an augmentation of the number and size of LDs when cells are treated with oleate overload compared to cells in resting conditions. Lipid accumulation in those cells is probably mediated by autophagy inhibition, leading to impaired lipolysis (Singh et al., 2009).

Interferons play a specific role in the generation of LDs, especially during viral infection. Interferon-stimulated genes (ISG) encode some important proteins that act as inhibitors of LD formation (Helbig et al., 2013; Peña Cárcamo et al., 2018; Bosch et al., 2020; An et al., 2022). One of those proteins is the Sterile Alpha Motif and Histidine-aspartate Domain containing protein 1 (SAMHD1). In an HCV infection model, cells that overexpress this protein had 50% less LDs compared to the control and, consequently, produced less virus. On the contrary, the knockdown of the SAMHD1 led to an increase in HCV core protein detection (An et al., 2022). Other ISG that influences LD formation is Viperin. In homeostatic conditions this protein is localized in the ER and is transported to LDs. Viperin also exerts an antiviral role, during infection by Junín mammarenovirus (Peña Cárcamo et al., 2018).

LDs are also the site of eicosanoid production since they are a reservoir of arachidonic acid (Moreira et al., 2009). In Caco2 cells, the presence of cyclooxygenase-2 (COX-2) and prostaglandin E₂ (PGE) was described and correlated to inflammation during colon cancer (Accioly et al., 2008). In oleic acid-treated IEC-6 cells, the formation of new LDs overlaps the compartmentalization of cytosolic PLA₂, with production and storage of PGE₂ within the LDs (Moreira et al., 2009). In the HL-60-derived neutrophils, treatment with Porphyromonas gengivalis led to an increased number of LDs, with a concomitant increase in Perilipin 3 protein. Interestingly, there is also an increase in PGE₂ production and release, which demonstrates that there is a relation between the production of LDs and its proteins, and the production and release of eicosanoids (Nose et al., 2013).

Lipids and lipid metabolism are crucial for normal cell functioning, mainly in cells that rely only on β-oxidation as a source of ATP. Subversion of β-oxidation and of functioning of FAT, FABP, and FATP are used by pathogens to acquire free FAs as carbon sources, for energy, and production of other molecules.

Intracellular pathogens evolved mechanisms to exploit cell FA metabolism and membrane lipids to favor their growth and survival. The strategies to accomplish this fate are well reported in the literature, and there are plenty of studies describing the exact mechanism used by those pathogens.

Considering that extracellular bacteria lack the machinery for lipid metabolism and production of cholesterol, the exploitation of lipids from the host’s cell membrane is used as the source of lipids that will compose the bacterial membrane. A close interaction between host cells and bacteria is needed to allow membrane lipids to interchange, and this interaction is mediated by lipid rafts present in both host cell and bacterial membrane.

To date, only a few works have been published addressing the use of lipids and the exploitation of lipid metabolism by extracellular pathogens. Those scarce, but relevant studies, however, shed light on the role of lipids in the interaction between extracellular pathogens and host cells, and point to the need for more experimental studies to uncover the pathways underlying these processes.

LP wrote the manuscript and conceived the figure. NC and AB revised it critically for intellectual content. All authors contributed to the article and approved the submitted version.