Hepatic transcriptome response to high dietary cholesterol intake in pig NAFLD model
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PROVIDER: PRJNA596671 | ENA |
REPOSITORIES: ENA
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Project description:The mechanisms by which cholesterol promotes NAFLD remain far less clear. Animal models are necessary to explore the pathogenesis and therapies of NAFLD. Several previous studies have shown that pig breeds can differ in their metabolic phenotype in response to high-energy diet. To investigate whether genetic background has profound effects on pig NAFLD phenotype and their metabolic response to dietary cholesterol intake, we performed RNA-Seq on liver tissues from two miniature pig breeds fed either standard or a high-fat and high-cholesterol diet for 6 months.
2022-12-15 | GSE142346 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, we assess the metabolic and hepatic effects of dietary amino acid (AA) source in Western diet (WD)-induced NAFLD in male and female mice. The AA source was either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD displayed glucose intolerance, fasting hyperglycemia, and insulin-resistance and developed NAFLD associated with changes in hepatic gene expression and dysbiosis. In contrast, males fed the AA-based WD showed no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females were protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Thus, free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex-specific manner.
2024-01-01 | GSE234591 | GEO
Project description:This data submission reports the effects of 12 weeks supplementaion of 10%w/v sucrose supplied in drinking water on the inguinal white adipose tissue mRNA profiles of male and female mice relative to control groups (littermates that received plain water instead). RNAseq was performed by Novogene and investigators performed all analyses downstream of readcount acquisition. Manuscript abstract: Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.
2021-03-01 | GSE151358 | GEO
Project description:Background: Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 ingredients: Hepar compositum (HC-24). Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis (next generation sequencing). Transcriptomics results were further substantiated with immunohistochemical and liver lipid analyses. Results: HFD feeding induced obesity and metabolic dysfunction that was associated with adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not affect total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes involved in inflammation (e.g. neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e. predicted effect on 'cholesterol' as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24. Conclusions: Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.
2021-03-01 | GSE163652 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the 2H2O-metabolic labeling approach to test the hypothesis that the reduced stability of oxidative phosphorylation proteins contributes to mitochondrial dysfunction in a diet-induced mouse model of NAFLD. A high fat diet containing cholesterol (a so-called Western diet (WD)) led to hepatic oxidative stress, steatosis, inflammation and mild fibrosis, all markers of NAFLD, in LDLR-/- mice. In addition, compared to controls, livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting reduced mitochondrial oxidative capacity. Proteome dynamics analysis revealed that mitochondrial dysfunction is associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41±0.46 vs. 5.15±0.49 day, P<0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome c oxidase subunit 4 isoform 1 of complex III (5.9 ± 0.1 vs 3.4 ± 0.8 day), ATP synthase subunit α (6.3±0.4 vs. 5.5±0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5±0.6 vs. 6.5±0.2 day) (P<0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities, suggesting that increased degradation of mitochondrial proteins contributed to hepatic mitochondrial dysfunction in NAFLD mice. Autophagy, but not proteasomal degradation, contributed to increased clearance of hepatic mitochondrial proteins in NAFLD mice. In conclusion, the proteome dynamics approach suggests that alterations in mitochondrial proteome dynamics is involved in hepatic mitochondrial dysfunction in NAFLD.
2018-11-21 | PXD008766 | Pride
Project description:Background Small intestine and liver greatly contribute to whole body lipid, cholesterol and phospholipid metabolism but to which extent cholesterol and phospholipid handling in these tissues is affected by high fat Western-style obesogenic diets remains to be defined. We therefore quantified cholesterol and phospholipid concentrations in intestine and liver and determined fecal neutral sterol and bile acid excretion in C57Bl/6N mice fed for 12 weeks either a cholesterol-free high carbohydrate control diet or a high fat diet containing 0.03 % (w/w) cholesterol. To identify underlying mechanisms of dietary adaptation in intestine and liver, changes in gene expression were assessed by microarray and qPCR profiling, respectively. Results Animals on high fat diet showed increased plasma cholesterol levels, associated with the higher dietary cholesterol supply, yet, significantly reduced cholesterol levels were found in intestine and liver. Transcript profiling revealed evidence that expression of numerous genes involved in cholesterol synthesis and uptake via LDL, but also in phospholipid metabolism, underwent compensatory regulations in both tissues. Alterations in glycerophospholipid metabolism were confirmed at the metabolite level by phospolipid profiling via mass spectrometry. Conclusions Our findings suggest that intestine and liver react to a high dietary fat intake by an activation of de novo cholesterol synthesis and other cholesterol-saving mechanisms, as well as with major changes in phospholipid metabolism, to accommodate to the fat load. The proximal part of the intestine of mice fed either a control or a high fat diet were analyzed. 5 replicates each.
2011-08-31 | E-GEOD-29748 | biostudies-arrayexpress
Project description:Inflammation, mediated by liver-resident Kupffer cells (KCs) and recruited infiltrating macrophages (IMs), plays a critical role in NAFLD pathogenesis. Cholesterol induces pro-inflammatory cytokine production by macrophages and has been identified as a key factor involved in progression from simple steatosis to NASH. In this study, using the fructose, palmitate, cholesterol & trans-fat (FPC) diet model which recapitulates human NAFLD, we aimed to determine the impact of cholesterol manipulation on NAFLD progression/regression and macrophage phenotype in vivo.The transcriptomic evaluation of hepatic macrophages from mice fed with FPC diet contained the highest concentration of cholesterol (1.25%) suggest these cells might contribute to liver inflammation, steatohepatitis, and hepatocarcinoma pathways during the progression phase.
2022-08-23 | GSE205776 | GEO
Project description:The study evaluated effects of dietary cholesterol (1.5%) in Atlantic salmon fed a plant based diet for 77 days. Cholesterol supplementation did not affect growth or organ weights of Atlantic salmon, but promoted induction of cholesterol and plant sterol efflux in the intestine, whereas sterol uptake was suppressed. Microarray analyses in the liver indicated decreased cholesterol biosynthesis and enhanced conversion to bile acids. The marked effect of cholesterol on bile acid synthesis suggests that dietary cholesterol can be used to stimulate bile acid synthesis in fish. The study clearly demonstrated how Atlantic salmon adjusted metabolic functions in response to the dietary load of cholesterol, and has expanded our understanding of sterol metabolism and turnover that adds to the knowledge of these processes in fish. Atlantic salmon received feeds based on plant ingredients with (CH) and without (K) supplementation of cholesterol. Liver samples were collected after 77 days. Five individuals from each group were analyzed with microarrays, pooled liver sample of salmon fed with commerical fish meal based feed was used as a reference.
2013-10-31 | E-GEOD-51887 | biostudies-arrayexpress
Project description:Background Small intestine and liver greatly contribute to whole body lipid, cholesterol and phospholipid metabolism but to which extent cholesterol and phospholipid handling in these tissues is affected by high fat Western-style obesogenic diets remains to be defined. We therefore quantified cholesterol and phospholipid concentrations in intestine and liver and determined fecal neutral sterol and bile acid excretion in C57Bl/6N mice fed for 12 weeks either a cholesterol-free high carbohydrate control diet or a high fat diet containing 0.03 % (w/w) cholesterol. To identify underlying mechanisms of dietary adaptation in intestine and liver, changes in gene expression were assessed by microarray and qPCR profiling, respectively. Results Animals on high fat diet showed increased plasma cholesterol levels, associated with the higher dietary cholesterol supply, yet, significantly reduced cholesterol levels were found in intestine and liver. Transcript profiling revealed evidence that expression of numerous genes involved in cholesterol synthesis and uptake via LDL, but also in phospholipid metabolism, underwent compensatory regulations in both tissues. Alterations in glycerophospholipid metabolism were confirmed at the metabolite level by phospolipid profiling via mass spectrometry. Conclusions Our findings suggest that intestine and liver react to a high dietary fat intake by an activation of de novo cholesterol synthesis and other cholesterol-saving mechanisms, as well as with major changes in phospholipid metabolism, to accommodate to the fat load.
2011-09-01 | GSE29748 | GEO
Project description:Prolonged intervention studies investigating molecular metabolism are necessary for a deeper understanding of dietary effects on health. Here we provide mechanistic information about metabolic adaptation to fat-rich diets. Healthy men ingested saturated (SFA) or poly unsaturated (PUFA) fat-rich diets for six weeks during weight maintenance. Hyperinsulinemic clamps combined with leg balance technique revealed unchanged peripheral insulin sensitivity, independent of fatty acid type. Both diets increased fat oxidation potential in muscle. Hepatic insulin clearance increased, while glucose production, de novo lipogenesis and plasma triacylglycerol decreased. High fat intake changed the plasma proteome in immune-supporting direction and the gut microbiome displayed changes at taxonomical and functional level with PUFA. In mice, eucaloric feeding of human PUFA and SFA diets lowered hepatic triacylglycerol content compared to low-fat fed control mice, and induced adaptations in the liver supportive of decreased gluconeogenesis and lipogenesis. Intake of fat-rich diets thus induces extensive metabolic adaptations enabling disposition of dietary fat without metabolic complications.
2018-10-11 | PXD010516 | Pride