Cholesterol accumulation as a driver of hepatic inflammation under translational dietary conditions can be attenuated by a multicomponent medicine
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ABSTRACT:
PROVIDER: PRJNA687010 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR13282400.fastq.gz | Fastqsanger.gz | |||
| SRR13282401.fastq.gz | Fastqsanger.gz | |||
| SRR13282402.fastq.gz | Fastqsanger.gz | |||
| SRR13282403.fastq.gz | Fastqsanger.gz | |||
| SRR13282404.fastq.gz | Fastqsanger.gz |
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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:BackgroundNon-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 natural ingredients: Hepar compositum (HC-24).MethodsLdlr-/-.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. Transcriptomics results were further substantiated with ELISA, immunohistochemical and liver lipid analyses.ResultsHFD feeding induced obesity and metabolic dysfunction including 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 alter total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes and proteins 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 CXCL1 ELISA, 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.ConclusionsFree 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.
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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:Intestinal cholesterol absorption is an important determinant of systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe, is a critical player in dietary cholesterol uptake. But how cholesterol moves within the cell downstream of NPC1L1 is unknown. Here we show that the nonvesicular sterol transporters Aster-B and -C cooperate with NPC1L1 to deliver dietary cholesterol from the gut lumen to the enterocyte ER for chylomicron packaging. Aster proteins are recruited to the enterocyte plasma membrane (PM) in response to NPC1L1-dependent cholesterol accumulation. Mice lacking Asters in intestine have impaired cholesterol absorption, and reduced plasma cholesterol. NanoSIMS imaging and tracer studies reveal delayed lipid trafficking into chylomicrons in Aster-deficient enterocytes. Interestingly, in addition to potently blocking NPC1L1, ezetimibe is also a low-affinity inhibitor of Aster-B and -C but not -A, and the structure of the Aster-C-ezetimibe complex reveals the basis for this selectivity. Our findings support a model in which NPC1L1 enriches dietary cholesterol at the apical PM, and ASTERs subsequently traffic this cholesterol to the ER. The findings identify the enterocyte Aster pathway as potential target for treatment of hypercholesterolemia. Alessandra Ferrari, PhD
2023-12-21 | GSE206780 | GEO
Project description:Dietary cholesterol promotes steatohepatitis-related hepatocellular carcinoma by inducing aberrant genomic expression and mutations
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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:IGNITE: Genomic Medicine Implementation - The Personalized Medicine Program
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Project description:IGNITE: Genomic Medicine Implementation - The Personalized Medicine Program
| PRJNA606621 | ENA
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:We investigated the effects of cholesterol on nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in diethylnitrosamine-injected mice fed high-fat high-cholesterol (HFHC) diet versus high-fat (HF) alone. mRNA microarray analysis was applied for expressional aberrations.
2018-09-27 | E-MTAB-6002 | biostudies-arrayexpress