Intestinal Cholesterol Research Articles

Cow's Milk Allergy May Induce Lipid Metabolism Disorder in BALB/c Mice via Exosomes.

Allergic diseases and lipid-metabolism-disorder-derived diseases are both significant public health issues. Recent studies have shown that exosomes are associated with the course of allergic diseases and are involved in lipid metabolism. In this study, exosomes derived from cow's milk allergic (CMA) mice medially loaded lesser proteins favoring cholesterol metabolism. The levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) in the serum were increased in the CMA mice, and hepatic lipid deposition was observed in the liver, but these phenomena were improved by inhibiting the exosome release. Specifically, the higher expression of the sterol regulatory element binding factor 2 (SREBP2) protein and HMGCR gene in the liver of CMA mice indicated an increase in cholesterol synthesis. NPC1L1 was also highly expressed in the small intestine of CMA mice, and fecal TC level was decreased, suggesting that the reabsorption of cholesterol was elevated. The biosynthesis of cholesterol, the reverse cholesterol transport (RCT) process, and the synthesis of bile acid in the liver were improved by inhibiting exosome release, as well as the reabsorption of cholesterol in the small intestine. This study has for the first time demonstrated the lipid metabolism disorder caused by CMA, especially the important role of exosomes in food allergies and lipid metabolism.

Therapeutic Role of Polyphenol Extract from Prunus cerasifera Ehrhart on Non-Alcoholic Fatty Liver.

Prunus cerasifera Ehrhart (P. cerasifera) flourishes uniquely in the arid landscapes of Xinjiang, China. Preliminary studies have revealed the therapeutic potential of its polyphenol extract (PPE) in mitigating liver lipid accumulation in mice fed a high-fat diet. We established a mouse model that was subjected to a continuous high-fat diet for 24 weeks and administered PPE to investigate the effects of PPE on cholesterol and BA metabolism in NAFLD mice. The results showed that PPE administration (200 and 400 mg/kg/day, BW) led to a reduction in liver TC, an increase in liver T-BAs, and normalization of the disrupted fecal BA profile. Concurrently, it decreased levels of lipotoxic BAs and inhibited hepatic cholesterol synthesis (evidenced by reduced HMGCR activity) and intestinal cholesterol absorption (indicated by lower ACAT2 levels) while enhancing intestinal cholesterol efflux (via LXRα, ABCA1, ABCG5, and ABCG8) and stimulating hepatic BA synthesis (CYP7A1, CYP27A1) and secretion (BSEP). PPE thus led to a significant reduction in lipotoxic BAs metabolized by gut microbiota and a downregulation of the BA secretion pathway under its influence. Our findings reveal the therapeutic effect of PPE on NAFLD mice via regulating cholesterol and BA metabolism, providing a theoretical basis for exploring the potential functions of P. cerasifera.

Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice

The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes. Male and female intestine-specific WASHC1-deficient mice (Washc1IKO) were challenged with either a standard chow diet or a high-cholesterol (1.25 %) diet (HCD). Washc1IKO mice fed a standard diet did not present any apparent phenotype, but when fed an HCD, their hepatic cholesterol levels were ~ 50 % lower compared to those observed in control mice. The intestinal cholesterol absorption was almost 2-fold decreased in Washc1IKO mice, which translated into increased fecal neutral sterol loss. The intestinal expression of cholesterogenic genes, such as Hmgcs1, Hmgcr, and Ldlr, was significantly higher in Washc1IKO mice than in control mice and correlated with increased whole-body de novo cholesterol synthesis, likely to compensate for impaired intestinal cholesterol absorption. Unexpectedly, the ratio of biliary 12α−/non-12α-hydroxylated bile acids (BAs) was decreased in Washc1IKO mice and reversing this reduced ratio by feeding the mice with the HCD supplemented with 0.5 % (w/w) sodium cholate normalized the improvement of hepatic cholesterol levels in Washc1IKO mice. Our data indicate that the intestinal WASH complex plays an important role in intestinal cholesterol absorption, likely by modulating biliary BA composition.

Multi-Omics Analysis to Understand the Effects of Dietary Proanthocyanidins on Antioxidant Capacity, Muscle Nutrients, Lipid Metabolism, and Intestinal Microbiota in Cyprinus carpio.

Proanthocyanidins (Pros), a natural polyphenolic compound found in grape seed and other plants, have received significant attention as additives in animal feed. However, the specific mechanism by which Pros affect fish health remains unclear. Therefore, the aim of this study was to investigate the potential effects of dietary Pro on common carp by evaluating biochemical parameters and multi-omics analysis. The results showed that Pro supplementation improved antioxidant capacity and the contents of polyunsaturated fatty acids (n-3 and n-6) and several bioactive compounds. Transcriptomic analysis demonstrated that dietary Pro caused an upregulation of the sphingolipid catabolic process and the lysosome pathway, while simultaneously downregulating intestinal cholesterol absorption and the PPAR signaling pathway in the intestines. Compared to the normal control (NC) group, the Pro group exhibited higher diversity in intestinal microbiota and an increased relative abundance of Cetobacterium and Pirellula. Furthermore, the Pro group had a lower Firmicutes/Bacteroidetes ratio and a decreased relative abundance of potentially pathogenic bacteria. Collectively, dietary Pro improved antioxidant ability, muscle nutrients, and the diversity and composition of intestinal microbiota. The regulation of lipid metabolism and improvement in muscle nutrients were linked with changes in the intestinal microbiota.

Totum-070, a Polyphenol-Rich Plant Extract, Prevents Hypercholesterolemia in High-Fat Diet-Fed Hamsters by Inhibiting Intestinal Cholesterol Absorption.

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, and hypercholesterolemia is a central risk factor for atherosclerosis. This study evaluated the effects of Totum-070, a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia. The molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced the total cholesterol (-41%), non-HDL cholesterol (-47%), and triglycerides (-46%) in a dose-dependent manner, compared with HFD. HFD-induced hepatic steatosis was also significantly decreased by Totum-070, an effect associated with the reduction in various lipid and inflammatory gene expression. Upon challenging with olive oil gavage, the post-prandial triglyceride levels were strongly reduced. The sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group and associated with reduction of intestinal cholesterol absorption. These effects were confirmed in the Caco2 cells, where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, a microbiota composition analysis revealed a strong effect of Totum-070 on the alpha and beta diversity of bacterial species and a significant decrease in the Firmicutes to Bacteroidetes ratio. Altogether, our findings indicate that Totum-070 lowers hypercholesterolemia by reducing intestinal cholesterol absorption, suggesting that its use as dietary supplement may be explored as a new preventive strategy for cardiovascular diseases.

Laminarin Reduces Cholesterol Uptake and NPC1L1 Protein Expression in High-Fat Diet (HFD)-Fed Mice.

Aberrantly high dietary cholesterol intake and intestinal cholesterol uptake lead to dyslipidemia, one of the risk factors for cardiovascular diseases (CVDs). Based on previous studies, laminarin, a polysaccharide found in brown algae, has hypolipidemic activity, but its underlying mechanism has not been elucidated. In this study, we investigated the effect of laminarin on intestinal cholesterol uptake in vitro, as well as the lipid and morphological parameters in an in vivo model of high-fat diet (HFD)-fed mice, and addressed the question of whether Niemann-Pick C1-like 1 protein (NPC1L1), a key transporter mediating dietary cholesterol uptake, is involved in the mechanistic action of laminarin. In in vitro studies, BODIPY-cholesterol-labeled Caco-2 cells were examined using confocal microscopy and a fluorescence reader. The results demonstrated that laminarin inhibited cholesterol uptake into Caco-2 cells in a concentration-dependent manner (EC50 = 20.69 μM). In HFD-fed C57BL/6J mice, laminarin significantly reduced the serum levels of total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). It also decreased hepatic levels of TC, TG, and total bile acids (TBA) while promoting the excretion of fecal cholesterol. Furthermore, laminarin significantly reduced local villous damage in the jejunum of HFD mice. Mechanistic studies revealed that laminarin significantly downregulated NPC1L1 protein expression in the jejunum of HFD-fed mice. The siRNA-mediated knockdown of NPC1L1 attenuated the laminarin-mediated inhibition of cholesterol uptake in Caco-2 cells. This study suggests that laminarin significantly improves dyslipidemia in HFD-fed mice, likely by reducing cholesterol uptake through a mechanism that involves the downregulation of NPC1L1 expression.

Cholesterol Behind the Whole Life of Humans

Cholesterol is a sterol, synthesized by animal cells and vital lipid molecule for human cells (animal) and is also a component of the diet, being present in food of animal origin. Its main function is to maintain the integrity and fluidity of cell membranes and to serve as a precursor for the synthesis of substance that are vital for the organism including steroid hormones, bile acids and vitamin D. animal cells acquire cholesterol from extracellular lipoprotein and form new synthesis of cells. Dietary cholesterol comes exclusively from animal sources, it is naturally present in our diet and tissues. Cholesterol is synthesized in the human body in order to maintain a stable peel when dietary intake is low, given the necessity for cholesterol, very effective intestinal uptake mechanisms bile acid and cholesterol reabsorption cycles exist1. Conversely carbohydrates are poorly absorbed and indeed rapidly excreted. Dietary cholesterol content does not significantly influence cholesterol value, which are regulated by various nutritional. Factors that influence cholesterol absorption (or) synthesis. Recent study data do not support a link between dietary cholesterol and cardio vascular diseases2.

Bile acids-mediated intracellular cholesterol transport promotes intestinal cholesterol absorption and NPC1L1 recycling

Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the A1272LAL residues dissociates from membrane, exposing the Q1277KR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.

Treatment of intestinal and liver features in cystic fibrosis mice by the osmotic laxative polyethylene glycol

BackgroundCystic Fibrosis (CF) is a genetic disease affecting multiple organs, primarily the lungs and digestive system. Improved pulmonary management significantly improved life expectancy of CF patients. As a result, extrapulmonary manifestations, including gastrointestinal and liver-related symptoms, have become more relevant. We previously reported that the osmotic laxative polyethylene glycol (PEG), which hydrates the CF gut, decreased fecal bile acid loss in a CF knockout mouse model. In the current study we investigated the effect of PEG on intestinal fat and cholesterol absorption and on CF-related liver features in a CF mouse model with the most common CF-causing mutation. MethodsCftrΔF508/ΔF508 (n=13) and wild-type (WT) (n=12) mice were treated with PEG for 2 weeks. The intestinal and hepatic effects of PEG were assessed by analysis of intestinal bile acid, cholesterol, and fat fluxes, transcriptome analysis as well as histology. ResultsPEG improved intestinal malabsorption of bile acids, fat, and cholesterol in CftrΔF508/ΔF508 mice. Transcriptome analysis showed that PEG partially restored the intestinal signaling of nuclear receptors RXR, FXR, and CAR/PXR, which are involved in bile acid and xenobiotic metabolism. PEG also reduced liver inflammation in CF mice as assessed by transcriptome and histological analyses. ConclusionsPEG, a non-absorbable osmotic laxative, improved intestinal nutrient absorption, intestinal bile acid and xenobiotic signaling, as well as CF-related liver features. These findings highlight the potential for osmotic laxation to improve gastrointestinal complications of CF in humans.

The TICE Pathway: Mechanisms and Potential Clinical Applications.

Transintestinal cholesterol excretion (TICE) is a non-biliary pathway that excretes excess cholesterol from the body through feces. This article focuses on the research progress of the TICE pathway in the last few years, including the discovery process of the TICE pathway, its molecular mechanism, and potential clinical applications. Cholesterol homeostasis is vital for cardiovascular diseases, stroke, and neurodegenerative diseases. Beyond the cholesterol excretion via hepatobiliary pathway, TICE contributes significantly to reverse cholesterol transport ex vivo and in vivo. Nuclear receptors are ligand-activated transcription factors that regulate cholesterol metabolism. The farnesoid X receptor (FXR) and liver X receptor (LXR) activated, respectively, by oxysterols and bile acids promote intestinal cholesterol secretion through ABCG5/G8. Nutrient regulators and intestinal flora also modulate cholesterol secretion through the TICE pathway. TICE allows direct elimination of plasma cholesterol, which may provide an attractive therapeutic targets. TICE pathway may provide a potential target to stimulate cholesterol elimination and reduce the risk of cardiovascular diseases.

Dietary propionate administration improves growth performance, hepatic lipid deposition, and intestinal activity of digestive enzymes, inflammation, bacterial population, and antioxidant capacity in rainbow trout, Oncorhynchus mykiss

The present study aimed to investigate the effects of dietary sodium propionate on growth performance, hepatic lipid deposition, and intestinal activity of digestive enzymes, inflammation, bacterial population, and antioxidant capacity in rainbow trout, Oncorhynchus mykiss. The fish were fed diets supplemented with 0 g/kg (CTL), 1 g/kg (P1), 2.5 g/kg (P2.5), or 5 g/kg (P5) sodium propionate for 70 days. The results showed significant (P < 0.05) linear or quadratic relationships between dietary sodium propionate levels and all tested parameters. Growth performance and feed efficiency significantly increased in the P1 and P2.5 treatments, but decreased in the P5 treatment, compared to the CTL group. Hepatosomatic index significantly decreased in the P1 and P2.5 treatments, but increased in the P5 treatment, compared to the CTL group. The P1 and P2.5 treatments exhibited significantly lower viscerosomatic indices than the CTL group. The P1 and/or P2.5 treatments exhibited significantly higher intestinal amylase, lipase, trypsin, chymotrypsin, superoxide dismutase (SOD), catalase (CAT), and lower intestinal malondialdehyde (MDA), plasma glucose, and triglyceride levels than the CTL treatment. On the other hand, the P5 treatment exhibited significant decrease in intestinal lipase, SOD, CAT, and higher intestinal MDA, plasma glucose, cortisol, triglyceride, and cholesterol levels than the CTL group. The intestinal total viable bacteria significantly decreased in the propionate treatments, and the lowest level was observed in the P2.5 treatment. The P1 and P2.5 treatments had significantly higher intestinal abundance of Lactobacillus sp. and lower Aeromonas hydrophila, Yersinia ruckeri, and Streptococcus iniae than the CTL group. The pathogenic bacteria showed significant elevations in the P5 treatment, compared to the CTL group. The propionate treatment groups showed significant up-regulations in intestinal heat shock protein 70 expression than the CTL group. The intestinal expression of tumor necrosis factor-alpha and interleukin-1 beta significantly decreased in the P1 and P2.5 treatments, while increased in the P5 treatment, compared to the CTL group. The intestinal expression of defensin significantly increased in the P1 and P2.5 treatments, while decreased in the P5 treatment, compared to the CTL group. In conclusion, dietary sodium propionate can improve the growth and intestinal health of rainbow trout. Based on the results, 2.5 g/kg sodium propionate is suitable for rainbow trout, but higher levels induce growth retardation, hepatic lipid accumulation, and intestinal oxidative stress, inflammation, and dysbiosis.

Pentapeptide IIAEK ameliorates cholesterol metabolism via the suppression of intestinal cholesterol absorption in mice.

Dietary protein-derived peptides are effective in improving dyslipidemia and hypercholesterolemia. We previously identified a novel cholesterol-lowering pentapeptide IIAEK from milk beta-lactoglobulin. However, it remains unclear whether IIAEK affects the micellar solubility of cholesterol and the bile acid-binding ability to lower cholesterol. Moreover, there is no direct evidence that IIAEK inhibits intestinal cholesterol absorption and affects hepatic cholesterol and fecal steroid excretion in vivo. Herein, we showed that IIAEK did not affect the micellar solubility of cholesterol and the bile acid-binding ability. However, we found that IIAEK decreased serum and liver cholesterol levels and increased fecal steroid excretion in mice. Interestingly, IIAEK markedly suppressed the intestinal absorption of [3H]-cholesterol in mice. In conclusion, we found that IIAEK ameliorated cholesterol metabolism by suppressing intestinal cholesterol absorption without affecting in vitro micellar solubility of cholesterol and the bile acid-binding ability in mice.

Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis.

Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

The modulatory effects on enterohepatic cholesterol metabolism of novel cholesterol-lowering peptides from gastrointestinal digestion of Xuanwei ham

The aim of this study was to investigate the effects and mechanism of in vitro protein digestive products of Xuanwei ham with different ripening periods on cholesterol metabolism and hypercholesterolemia. The results showed that compared with other gastrointestinal digestion (GID) groups, the GID group of Xuanwei ham with 3-year ripening period (XWH3-GID) inhibited the expression of Niemann-Pick C1-like 1 (NPC1L1) and acetyl-CoA acetyltransferase 2 (ACAT2) through hepatocyte nuclear factor 1-alpha (HNF-1α), which in turn effectively inhibited cholesterol absorption in Caco-2 cell monolayers. Following absorption by Caco-2 cell monolayers, the XWH3-GID group suppressed the expression and secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) via HNF-1α, which enhanced the protein expression and fluorescence intensity of low density lipoprotein receptor (LDLR) on the HepG2 cell membrane, and thus promoted the uptake of low density lipoprotein (LDL). Importantly, three novel peptides (LFP, PKF and VPFP) derived from titin were identified after intestinal epithelial transport in the XWH3-GID group, which could exert cholesterol-lowering effects through inhibiting intestinal cholesterol absorption and promoting peripheral hepatic LDL uptake, and effectively ameliorate western diet-induced hypercholesterolemia in ApoE-/- mice. These results suggest that Xuanwei ham with 3-year ripening period can be used as a source of cholesterol-lowering peptides and has potential to intervene in hypercholesterolemia.

High-fat diet impact on intestinal cholesterol conversion by the microbiota and serum cholesterol levels

Cholesterol-to-coprostanol conversion by the intestinal microbiota has been suggested to reduce intestinal and serum cholesterol availability, but the relationship between intestinal cholesterol conversion and the gut microbiota, dietary habits, and serum lipids has not been characterized in detail. We measured conserved proportions of cholesterol high and low-converter types in individuals with and without obesity from two distinct, independent low-carbohydrate high-fat (LCHF) dietary intervention studies. Across both cohorts, cholesterol conversion increased in previous low-converters after LCHF diet and was positively correlated with the fecal relative abundance of Eubacterium coprostanoligenes. Lean cholesterol high-converters had increased serum triacylglycerides and decreased HDL-C levels before LCHF diet and responded to the intervention with increased LDL-C, independently of fat, cholesterol, and saturated fatty acid intake. Our findings identify the cholesterol high-converter type as a microbiome marker, which in metabolically healthy lean individuals is associated with increased LDL-C in response to LCHF.

Lactobacillus reuteri NCIMB 30242 (LRC) Inhibits Cholesterol Synthesis and Stimulates Cholesterol Excretion in Animal and Cell Models.

In this study, we evaluated the effects of Lactobacillus reuteri NCIMB (LRC™) supplementation on hypercholesterolemia by researching its effects on cellular cholesterol metabolism in hypercholesterolemic rats (KHGASP-22-170) and HepG2 cell line. Rats were separated into six groups after adaptation and were then fed a normal control (NC), a high-cholesterol diet (HC), or a HC supplemented with simvastatin 15 mg/kg body weight (positive control [PC]), LRC 1 × 109 colony-forming units (CFU)/rat/day, LRC 4 × 109 CFU/rat/day, or LRC 1 × 1010 CFU/rat/day (1 × 109, 4 × 109, or 1 × 1010). The rats were dissected to study the effects of LRC on cholesterol metabolism and intestinal excretion at the end of experimental period. We discovered that LRC mainly participated in the restraint of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the uptake of low-density lipoprotein (LDL) cholesterol into tissues, partially in the transport of cholesteryl esters into high density lipoprotein for maturation, and intestinal excretion of cholesterol. These results are supported by the expression of transcription factors and enzymes such as HMG-CoA reductase, SREBP2, CYP7A1, CETP, and LCAT in both messenger RNA (mRNA) and protein levels in serum and hepatic tissue. Furthermore, the LRC treatment in HepG2 significantly reduced the mRNA expression of HMG-CoA reductase, SREBP2, and CEPT and significantly increased the mRNA expression of LDL-receptor, LCAT, and CYP7A1 at all doses. Hence, we suggest that LRC supplementation could alleviate the serum cholesterol level by inhibiting the intracellular cholesterol synthesis, and augmenting excretion of intestinal cholesterol.

TOTUM-070, A combination of plant extracts, reduces hypercholesterolemia trough inhibition of intestinal cholesterol absorption in hamsters and human CACO2 cells

TOTUM-070, A combination of plant extracts, reduces hypercholesterolemia trough inhibition of intestinal cholesterol absorption in hamsters and human CACO2 cells

Can human trans intestinal cholesterol excretion be stimulated using ursodeoxycholic acid and ezetimibe: A randomized placebo controlled cross-over study

Can human trans intestinal cholesterol excretion be stimulated using ursodeoxycholic acid and ezetimibe: A randomized placebo controlled cross-over study

Fructose consumption during pregnancy increases intestinal cholesterol absorption in rat male descendants treated with a high-fructose high-cholesterol diet

Fructose consumption during pregnancy increases intestinal cholesterol absorption in rat male descendants treated with a high-fructose high-cholesterol diet

Intestinal Pgc1α ablation protects from liver steatosis and fibrosis

The gut-liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic steatosis and a progressive increase of inflammation and fibrosis, culminating in metabolic dysfunction-associated steatohepatitis. Peroxisome proliferator-activated receptor-gamma coactivator 1α (Pgc1α) is a transcriptional co-regulator of mitochondrial activity and lipid metabolism. Here, the intestinal-specific role of Pgc1α was analysed in liver steatosis and fibrosis. We used a mouse model in which Pgc1α was selectively deleted from the intestinal epithelium. We fed these mice and their wild-type littermates a Western diet to recapitulate the major features of liver steatosis (after 2 months of diet) and metabolic dysfunction-associated steatohepatitis (after 4 months of diet). The chow diet was administered as a control diet. In humans and mice, low expression of intestinal Pgc1α is inversely associated with liver steatosis, inflammation, and fibrosis. Intestinal disruption of Pgc1α impairs the transcription of a wide number of genes, including the cholesterol transporter Niemann-Pick C1-like 1 (Npc1l1), thus limiting the uptake of cholesterol from the gut. This results in a lower cholesterol accretion in the liver and a decreased production of new fatty acids, which protect the liver from lipotoxic lipid species accumulation, inflammation, and related fibrotic processes. In humans and mice, intestinal Pgc1α induction during Western diet may be another culprit driving hepatic steatosis and fibrosis. Here, we show that enterocyte-specific Pgc1α ablation protects the liver from steatosis and fibrosis by reducing intestinal cholesterol absorption, with subsequent decrease of cholesterol and de novo fatty acid accumulation in the liver. Liver diseases result from several insults, including signals from the gut. Although the incidence of liver diseases is continuously increasing worldwide, effective drug therapy is still lacking. Here, we showed that the modulation of an intestinal coactivator regulates the liver response to a Western diet, by limiting the uptake of dietary cholesterol. This results in a loweraccumulation of hepatic lipids together with decreased inflammation and fibrosis, thus limiting the progression of liver steatosis and fibrosis towards severe end-stage diseases.