When fat meets the gut—focus on intestinal lipid handling in metabolic health and disease
2022; Springer Nature; Volume: 14; Issue: 5 Linguagem: Inglês
10.15252/emmm.202114742
ISSN1757-4684
AutoresMagdalena Wit, Jonathan Trujillo Viera, Akim Strohmeyer, Martin Klingenspor, Mohammed K. Hankir, Grzegorz Sumara,
Tópico(s)Diet, Metabolism, and Disease
ResumoReview19 April 2022Open Access When fat meets the gut—focus on intestinal lipid handling in metabolic health and disease Magdalena Wit Magdalena Wit Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland Search for more papers by this author Jonathan Trujillo-Viera Jonathan Trujillo-Viera Rudolf-Virchow-Zentrum, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany Search for more papers by this author Akim Strohmeyer Akim Strohmeyer orcid.org/0000-0003-3650-9661 Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Freising, Germany EKFZ - Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University of Munich, Munich, Germany ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany Search for more papers by this author Martin Klingenspor Corresponding Author Martin Klingenspor [email protected] orcid.org/0000-0002-4502-6664 Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Freising, Germany EKFZ - Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University of Munich, Munich, Germany ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany Search for more papers by this author Mohammed Hankir Corresponding Author Mohammed Hankir [email protected] orcid.org/0000-0001-5218-9683 Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany Search for more papers by this author Grzegorz Sumara Corresponding Author Grzegorz Sumara [email protected] orcid.org/0000-0003-1502-6265 Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland Search for more papers by this author Magdalena Wit Magdalena Wit Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland Search for more papers by this author Jonathan Trujillo-Viera Jonathan Trujillo-Viera Rudolf-Virchow-Zentrum, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany Search for more papers by this author Akim Strohmeyer Akim Strohmeyer orcid.org/0000-0003-3650-9661 Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Freising, Germany EKFZ - Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University of Munich, Munich, Germany ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany Search for more papers by this author Martin Klingenspor Corresponding Author Martin Klingenspor [email protected] orcid.org/0000-0002-4502-6664 Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Freising, Germany EKFZ - Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University of Munich, Munich, Germany ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany Search for more papers by this author Mohammed Hankir Corresponding Author Mohammed Hankir [email protected] orcid.org/0000-0001-5218-9683 Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany Search for more papers by this author Grzegorz Sumara Corresponding Author Grzegorz Sumara [email protected] orcid.org/0000-0003-1502-6265 Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland Search for more papers by this author Author Information Magdalena Wit1, Jonathan Trujillo-Viera2, Akim Strohmeyer3,4,5, Martin Klingenspor *,3,4,5, Mohammed Hankir *,6 and Grzegorz Sumara *,1 1Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland 2Rudolf-Virchow-Zentrum, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany 3Chair for Molecular Nutritional Medicine, Technical University of Munich, TUM School of Life Sciences Weihenstephan, Freising, Germany 4EKFZ - Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University of Munich, Munich, Germany 5ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany 6Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany *Corresponding author. Tel: +49 08161 712386; E-mail: [email protected] *Corresponding author. Tel: +49 931 201 31728; E-mail: [email protected] *Corresponding author. Tel: +48 22 5892 190; E-mail: [email protected] EMBO Mol Med (2022)e14742https://doi.org/10.15252/emmm.202114742 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract The regular overconsumption of energy-dense foods (rich in lipids and sugars) results in elevated intestinal nutrient absorption and consequently excessive accumulation of lipids in the liver, adipose tissue, skeletal muscles, and other organs. This can eventually lead to obesity and obesity-associated diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, as well as aggravate inflammatory bowel disease (IBD). Therefore, targeting the pathways that regulate intestinal nutrient absorption holds significant therapeutic potential. In this review, we discuss the molecular and cellular mechanisms controlling intestinal lipid handling, their relevance to the development of metabolic diseases, and emerging therapeutic strategies. Glossary The intestinal wall The wall of the intestine consists of four layers; mucosa (containing epithelial cells and responsible for selective nutrient absorption), submucosa (supportive layer of collagen-rich extracellular matrix), muscular layer (promoting gut motility), and adventitia (layer of loose connective tissue). The mucosa contains single-cell layer folded in the structure termed as Villus which increases the absorptive surface of the intestine. The intestinal epithelium Multiple cell types build the intestinal epithelium and altogether originate from the stem cells in Crypts. Among them, enterocytes are the principal cell type responsible for lipid and other nutrient absorption. Goblet cells are responsible for the secretion of mucus to the intestinal lumen, Paneth, Microfold, and Tuft cells are responsible for immune response, different subtypes of Enteroendocrine cells secrete multiple hormones, including glucagon-like peptide 1 (GLP-1), while functions of the Cup cells are not well defined. Introduction The global incidence of obesity continues to rise, with recent estimates that a quarter of the world's population is affected. When considering the root causes of obesity, changes in the environment, rather than in our genetics, are largely to blame (Haslam & James, 2005). Modern jobs are generally less laborious, while a sedentary way of life has become more common (Haslam & James, 2005). Additionally, the mass production of ultra-processed, energy-dense foods has meant that our average daily caloric intake has increased by approximately 500 kilocalories (kcal) per day from 1970 to 2000 in the United States alone (Haslam & James, 2005). It is not simply this increase in total calories consumed that is the problem however, but rather where those calories come from that seems to matter most. Indeed, studies in mice suggest that dietary fat, as opposed to other nutrients, is the major contributor to excess calorie intake and weight gain (Hu et al, 2018). Moreover, clinical evidence suggests that a low-fat diet lowers blood sugar and cholesterol more effectively than a low-carbohydrate one (Hall et al, 2015). Metabolic syndrome is characterized by a chronic, low-grade inflammation (meta-inflammation) induced by over-nutrition and obesity (Hotamisligil, 2006). Thus, indirectly, intestinal lipid absorption contributes to and may exacerbate this state. The key mediators of meta-inflammation are macrophages dispersed within the adipose tissue, liver, intestine, and skeletal muscles (Li et al, 2018). Obesity-associated alterations in the gut result in increased intestinal permeability and infiltration of bacteria into lamina propria (Cani et al, 2008; Amar et al, 2011), and macrophages that reside in the subepithelial layer of the intestine are activated by bacterial products (e.g. LPS), which is followed by the onset of metabolic disorders and chronic inflammation (Cani et al, 2008; Amar et al, 2011). Finding ways to interfere with fat digestion would therefore appear to be a suitable approach to treat obesity and its life-threatening comorbidities including type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular diseases, and possibly inflammatory disorders (IBD, meta-inflammation) as well as cancer (Fig 1). As outlined briefly in Fig 2, the digestion and absorption of fat is a complex process involving a number of steps and multiple rate-limiting enzymes (Hussain, 2014; Xiao et al, 2018; Ko et al, 2020). Also, the unique composition of the intestinal wall and whole digestive system defines the efficiency of lipid absorption (Aliluev et al, 2021). Figure 1. Mechanisms induced by dietary lipid overload leading to the development of metabolic diseases Food-derived fats are efficiently absorbed in the small intestine and distributed among peripheral tissues. Supplied in excess, lipids are stored in adipose tissue thus increasing body fat mass. The imbalance between the uptake of fatty acids (FA) by the liver and insufficient lipid disposal leads to non-alcoholic fatty liver disease (NAFLD). Systematically released from adipose tissue, FA (together with hormones, cytokines, and pro-inflammatory factors) cause peripheral insulin resistance and contribute to pancreatic β-cells impairment and development of type 2 diabetes. Hyperlipidemia is also an elementary risk factor for atherosclerotic plaques formation. The contribution of overload of intestinal tissue with lipids to the incidence of colorectal cancer and inflammatory bowel disease (IBD) is still not fully defined. Download figure Download PowerPoint Figure 2. Processing of dietary lipids for chylomicrons synthesis Food-derived lipids, in large part composed of triglycerides (TG), are emulsified by bile acid salts in the intestinal lumen to form micelles, aiding pancreatic lipase to hydrolyze TG. Final products of lipids digestion, free fatty acids (FA), and monoglycerides (MG) cross the apical membrane of the enterocyte via passive diffusion or this process is mediated by fatty acid transport protein 4 (FATP4) or CD36. Upon entering, FAs and MG are bound by fatty acid-binding proteins (L-FABP and I-FABP) and retinol-binding protein 2 (RBP2), respectively, and destined for TG re-synthesis. FA re-esterification is performed by subsequent action of monoacylglycerolacyl transferases (MGAT1, 2) and diacylglycerol acyltransferases (DGAT1, 2). Diacylglycerol utilized in the process can be derived from the glycerol-3 phosphate pathway. This process can be blocked upon AIDA-mediated endoplasmic reticulum-associated degradation (ERAD) of MGAT2, DGAT2, and glycerol-3-phosphate acyltransferase 3 (GPAT3). In the endoplasmic reticulum (ER), TG are loaded into apolipoprotein B48 (APOB48)-containing lipoprotein particle by microsomal transfer protein (MTTP); thus, a pre-chylomicron (pre-CM) forms, and another apolipoprotein, APOA4, is attached. Pre-CM are transported from ER via pre-chylomicron transport vesicles (PCTV) and fuse with the Golgi apparatus in the coat protein complex II (COPII)-dependent manner. Mature chylomicrons (CM) are secreted via exocytosis and taken up by the local lymphatic vessel. Pharmacological agents, targeting indicated pathways, are in pink frames. Download figure Download PowerPoint From the onset, it should be mentioned that the idea of interfering with lipid digestion for therapeutic purposes (such as achieving weight loss) is not a new one. Orlistat, which limits 30% of intestinal fat absorption by inhibiting the lipases that breakdown triglycerides (TG) (Zhi et al, 1994), was among the earliest anti-obesity drugs approved by the FDA in 1999 (Aaseth et al, 2021) but it only causes relatively modest weight loss in obese individuals after a year of the treatment (approximately 5% compared with placebo) (Sjöström et al, 1998). This is considerably lower than the 20–30% weight loss achieved during that time frame by the gold-standard bariatric surgery (Maciejewski et al, 2016) and the stable glucagon-like peptide 1 (GLP-1) analogue semaglutide (Wilding et al, 2021). However, recent preclinical data suggest that bariatric surgery itself causes weight loss through a complex malabsorptive mechanism (Ding et al, 2021) attesting to the potential of targeting intestinal lipid digestion to treat obesity and other metabolic diseases. It should also be mentioned that dietary lipid overload is an independent risk factor for the development of inflammatory bowel disease (IBD) (Gruber et al, 2013; Luck et al, 2015) and colorectal cancer (Bardou et al, 2013). Additionally, diets rich in fat induce dysbiosis which has been implicated in the pathogenesis of gastrointestinal cancers (Font-Burgada et al, 2016; Murphy et al, 2018). These findings have led to the idea that targeting intestinal fat processing can possibly also treat IBD and gastrointestinal cancers (Fig 1). In this review, we concentrate on the direct molecular regulators of TG processing machinery in the small intestine and their impact on the development of multiple metabolic diseases. We start with presenting human data on how intestinal fat absorption shows major inter-individual variability and how this could potentially be exploited therapeutically. We then extensively discuss the processes regulating the partition of the absorbed lipids between chylomicron (CM)-mediated secretion and storage in the lipid droplet (LD). We also focus on the mechanisms regulating CM lipidation and transfer to the lymphatic system. We have largely omitted discussion on the processes regulating digestion, uptake, and re-synthesis of TG (focusing only on the most recent concepts) and their role in the development of rare genetic diseases associated with mutations in key lipid processing enzymes, which were recently reviewed (Ko et al, 2020). We have also omitted other aspects of gut metabolism like the role of gut-derived hormones, or cholesterol processing on the regulation of metabolic homeostasis. These aspects are extensively covered in (Hussain, 2014; Xiao et al, 2018; Ko et al, 2020). Susceptibility to weight gain: argument for the role of intestinal lipid absorption When it comes to human gastrointestinal physiology, surprisingly limited information is available on the absorption efficacy of ingested food, especially dietary lipids. In general, the human gut exhibits remarkably high absorption efficiency with more than 90% of gross food energy absorbed by gastrointestinal epithelial cells and transported into the body (Southgate & Durnin, 1970; Heymsfield et al, 1981). Correspondingly, less than 10% of gross food energy is lost by fecal excretion in healthy adults. To balance daily energy expenditure, this means that a normal weight individual metabolizing 10,800 kJ (~ 2,600 kcal) per day should ingest 12,000 kJ (~ 2,900 kcal) of gross food energy. However, substantial inter-individual variation in absorption efficiencies exists and can range from 2 to 9% of gross food energy excreted in stool (Heymsfield & Pietrobelli, 2011; Figs 3 and 4). In one study, it was found that young men and women excreted 2.4–8.9 and 1.9–7.6 g/day, respectively, which largely exceeded their corresponding range in dietary fat intake, when fed a balanced (hospital) diet (Southgate & Durnin, 1970). A similar range was also found during baseline run-in periods in clinical trials addressing the effects of orlistat on lipid absorption and body weight (Fig 3; Hartmann et al, 1993; Hussain et al, 1994). Although the cohorts in these studies were relatively small and a systematic assessment of inter-individual variation is lacking, between-subject variability in absorption efficiency appeared to be impressively consistent. Interestingly, there is preliminary evidence suggesting low fecal energy excretion in obese vs. lean subjects (Webb & Annis, 1983) raising the possibility that higher intestinal lipid absorption is a causal factor of weight gain although these findings could not be confirmed in a more recent study (Jumpertz et al, 2011). Nevertheless, dietary interventions or manipulation of gut microbiota composition are associated with altered intestinal absorption efficiency without diluting the individual trait (Casper et al, 1990; Jumpertz et al, 2011). Figure 3. Interindividual variation in fecal fat excretion at base line and upon application of orlistat Each dot represents the amount of daily fat excretion from patients in two independent studies (Hartmann et al, 1993; Hussain et al, 1994), receiving placebo or orlistat (120 mg/day) and fed with standardized hospital diet. Download figure Download PowerPoint Figure 4. Inter-individual variability in energy intake, excretion, and expenditure in average healthy men The figure represents a simplified overview of the daily energy balance and inter-individual variations in the energy utilized for different physiological processes. Please note that relatively small, natural variation in energy exertion or expenditure might accumulate over a longer period (the estimation on the illustration was calculated for one year), resulting in leanness or obesity. Download figure Download PowerPoint Personalized approaches can by extension be envisaged in which intestinal lipid absorption is decreased in individuals with high vs. low fecal fat (energy) excretion and who would be in a more a positive energy balance. At 12,000 kJ gross energy intake, assuming 2–3% urinary energy excretion, individuals with high vs. low absorption efficacy would gain 660 kJ (200 kcal) vs. −180 kJ (43 kcal) metabolizable energy per day. These differences in energy balance, though small on a daily basis, could potentially cumulate over the year amounting to either an increase (+6 kg) or a decrease (−1.5 kg) in total body fat mass (50.2 MJ/kg and 39.4 MJ/kg) for fat mass gain and loss, respectively (Forbes, 1990; Elia & Livesey, 1992). The substantial range of intestinal fat absorption efficiencies strongly suggests that this physiological trait is susceptible to interventions (Fig 4). However, this would require the development of a standardized methodology that would allow an assessment of intestinal lipid absorption efficiency in patients. Impact of gut microbiota composition and metabolism on lipid absorption Investigating host and microbiota interactions in the regulation of lipid absorption is another emerging concept that deserves consideration. It was first reported in 2007 that germ-free mice are resistant to diet-induced obesity when fed a Western-type HFD (Bäckhed et al, 2007). Follow-up studies demonstrated that this phenotype is dependent on the quality and composition of the experimental HFD (Fleissner et al, 2010). To this end, the dietary fat source was identified as a driver for resistance with potential implications of dietary cholesterol (Kübeck et al, 2016). The latter study demonstrated that germ-free mice presented attenuated diet-induced obesity and increased fecal fat excretion when fed a HFD based on animal fat (lard), in contrast to plant fat (palm oil), while in conventional mice no differential impact of the fat source was observed. The complex interplay of diet and microbiota in regulating the efficacy of lipid absorption, metabolism, and energy balance of the host is gaining further attention. Microbiota signatures and metabolic pathways can affect these processes by different means. The contribution of the gut microbiota to host lipid metabolism and systemic host lipidome is directly measurable in different compartments like plasma and liver (Kindt et al, 2018), or different intestinal segments (Liebisch et al, 2021). HFD feeding in mice causes specific shifts in the jejunal microbiota, creating a specific HFD microbial signature. When transferred into germ-free mice, this HFD signature increases lipid uptake not only on a HFD but also on a regular low-fat diet, thus demonstrating a diet-independent capability of the small intestinal microbiota to impact lipid absorption (Martinez-Guryn et al, 2018). This is likely due to distinct metabolic pathways associated with altered microbiota signatures, even maintained without continued HFD feeding. Bacterial metabolites, like L-lactate or acetate, are able to directly affect the lipid metabolism of enterocytes by inhibiting CM secretion through different mechanisms (Araújo et al, 2020). Moreover, short-chain fatty acids generated by bacterial fermentation of dietary fiber enter the portal circulation and serve as precursors for hepatic synthesis of long-chain fatty acids (Kindt et al, 2018). Some bacterial taxa, such as Lactobacillaceae, metabolize dietary polyunsaturated fatty acids (PUFA) in defense of antimicrobial toxicity. In mice fed a HFD supplemented with the omega-6 PUFA linoleic acid, diet-induced obesity, adipose tissue inflammation, and glucose tolerance were improved. These beneficial metabolic effects were conveyed by the hydroxylation of linoleic acid to 10-hydroxy-cis-12-octadecenoic acid (HYA). This metabolite stimulated glucagon-like peptide 1 (GLP1) secretion from enteroendocrine cells and improved intestinal peristalsis via prostaglandin EP3 receptor (EP3), associated with lowered intestinal lipid absorption. Mono-association of germ-free mice with a HYA-producing bacterial strains confirmed the beneficial microbial impact (Miyamoto et al, 2019). Information regarding the human situation remains scarce, mainly due to the poor accessibility of the small intestine. Nevertheless, mechanistic murine studies pave way for new therapeutic approaches using pre- or probiotics. Support comes from a recent clinical trial on patients treated with Akkermansia muciniphila, a bacterium which improves gut barrier function and is known to be involved in lipid metabolism (Plovier et al, 2017; Xu et al, 2020), showing that it safely attenuated aspects of the metabolic syndrome (Depommier et al, 2019). Transport of lipid through the apical membrane as a target for pharmacological intervention Despite the relatively poor profile of orlistat (due to low weight loss efficacy with accompanying side effects) mentioned earlier, the approach of reducing intestinal fat absorption to treat metabolic disease has undergone somewhat of a renaissance in recent years and several novel candidate molecules have shown promise in preclinical studies. For example, the C22 omega-3 fatty acid derivative C22:6N-acyl taurine (NAT) improves fatty liver in mice by reducing intestinal TG breakdown and absorption (Fig 2) (Grevengoed et al, 2021). The farnesoid X receptor agonist GSK2324 has also been shown to improve fatty liver in mice by reducing intestinal fat absorption through modulating intestinal bile acid composition (Fig 2) (Clifford et al, 2021). When designing drugs that target intestinal fat absorption, a thorough understanding of the molecular processes involved is essential. The initial digestion of ingested TG into fatty acids (FA), monoglycerides (MG) and glycerol starts in the mouth and continues in the stomach by the action of lingual lipase and gastric lipase, respectively (Figs 1 and 2). The remaining and majority of TG digestion then takes place in the small intestine largely by the action of pancreatic lipase (Hussain, 2014). The MG and FA generated by lipases gain entrance into enterocytes by a combination of active transport and passive diffusive mechanisms. The two main proteins implicated in intestinal fatty acid uptake are fatty acid transport protein 4 (FATP4) and a cluster of differentiation 36 (CD36) (Fig 2). However, genetic experiments on mice suggest that both proteins play a minor or redundant role in intestinal lipid absorption (Goudriaan et al, 2002; Drover et al, 2005; Shim et al, 2009). Studies on the regulation of membrane fluidity (referring to the viscosity which determines diffusion rate of biomolecules within the plasma membrane) have provided insight into how passive diffusion might play the dominant role in intestinal fat absorption. Lysophosphatidylcholine acyltransferase (LPCAT3) catalyzes the addition of polyunsaturated FA to lysophosphatidylcholine (LPC) to form PUFA-containing phosphatidylcholine (PC) (which changes the membrane viscosity) (Zhao et al, 2008; Rong et al, 2013). It was found that LPCAT3-deficient mice weaned onto a high-fat diet die within a few weeks largely due to the reduced uptake of lipids into enterocytes (Li et al, 2015). Remarkably, this lethal phenotype can specifically be rescued by the oral gavage of olive oil supplemented with PCs (Li et al, 2015). In contrast, enterocyte-specific deletion of LPCAT3 in mice are viable when weaned onto a low-fat diet (Wang et al, 2016). These mice nevertheless show reduced serum TG and cholesterol levels, again pointing to an intestinal fat absorption defect (Wang et al, 2016). Indeed, when placed on a medium-fat diet, enterocyte-specific LPCAT3-deficient mice exhibit weight loss associated with higher fecal TG content, reduced uptake of FA into enterocytes, and lower levels of various PC species in enterocyte membranes causing them to be less dynamic (Wang et al, 2016). Similar to the case for global LPCAT3-deficient mice (Li et al, 2015), these defects can be rescued upon administration of polyunsaturated PC (Wang et al, 2016). These findings suggest that the graded inhibition of intestinal LPCAT3 could be exploited to treat obesity by reducing intestinal fat absorption through regulating enterocyte membrane fluidity. Intestinal TG re-synthesis as a new strategy to fix metabolism When FAs gain entrance into the enterocyte, they are rapidly bound to intestinal and liver fatty acid-binding proteins (I-FABP and L-FABP, respectively), which shuttle them to the ER. Loss of function studies in mice have provided insight into the negative roles played by I-FABP and L-FABP in regulating intestinal function and metabolic health. Specifically, deletion of I-FABP2 in APOE-deficient mice (a model for hyperlipidemia and hypercholesterolemia) resulted in the reduction of inflammation and progression of atherosclerosis due to the improvement in intestinal barrier integrity (Zhang et al, 2020). Similarly, deletion of L-FABP in a mouse model of colorectal adenomas formation resulted in a reduction of polyps size and alteration of the intestinal lipidome (Dharmarajan et al, 2013). Beyond their role in enterocytes, FABPs are also secreted into the general circulation. It has been shown that plasma levels of I-FABP in humans correlate positively not only with the levels of circulating TG and cholesterol as well as the degree of atherosclerosis in the carotid artery but is also an early marker of ulcerative colitis (Wiercinska-Drapalo et al, 2008; Zhang et al, 2020). Altogether, these findings position FABPs as potential targets for pharmacological intervention for multiple conditions. Unlike FA, MG can have one of two fates when inside the enterocyte. They can either be degraded by the action of monoglyceride lipase (MGL) into FAs and glycerol, or can be sequestered by retinol-binding protein 2 (RBP2) (Fig 2; Lee et al, 2020). Remarkably, both processes have been shown to have a major impact on whole body metabolic status. Enterocyte-specific overexpression of MGL in mice results in decreased MG in the small intestine and weight gain (Chon et al, 2012), while MGL-deficient mice gain less weight on a HFD despite increased food intake and have improved oral glucose tolerance (Douglass et al, 2015). On the other hand, whereas RBP2-deficient mice have increased MG in the small intestine (similar to MGL-deficient mice) (Douglass et al, 2015), they are susceptible to obesity due to reduced energy expenditure and increased food intake (Lee et al, 2020). This unexpected metabolic phenotype might be due to the increased release of gastric inhibitory polypeptide from enteroendocrine cells which is known to promote weight gain (Lee et al, 2020). These findings highlight an interesting difference with enterocyte-specific deletion of LPCAT3 in mice on HFD, who have severely reduced food intake and body weight due to increased GLP-1 release from enteroendocrine cells (Wang et al, 2016). Such studies indicate that intestinal fat digestion and absorption is tightly interconnected with the endocrine function of the digestive system which is especially relevant in the context of the development of therapies to treat metabolic diseases. Once FA and MG reach the ER in enterocytes, they are re-esterified by the concomitant action of monoacylglycerol acyltransferase 2 (MGAT2), glycerol-3-phosphate (G3P), and acyl-CoA: diacylglycerol acyltransferases 1/2 (DGAT1/2) in enterocytes (Fig 2). Multiple studies have proven (reviewed in Ko et al (2020)) that while these enzymes are relevant for the development of obesity, targeting any single component of this molecular machinery is not sufficient to effectively treat metabolic diseases. Therefore, a multipronged approach might be ideal to achieve amelioration of obesity and associated diseases. Misfolded pr
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