Role of Nrf2 in the alteration of cholesterol and bile acid metabolism-related gene expression by dietary cholesterol in high fat-fed mice

Abstract Background The role of gut microbes involved in bile acid metabolism and their impact on mucosal immune regulation is beginning to be appreciated. For instance, changes in microbial bile salt hydrolase (BSH) activity which deconjugates bile acids in the gastrointestinal tract of gnotobiotic mice, significantly alters gene expression patterns of immune-related genes in ileum. Moreover, bile acid dysmetabolism may participate in the chronic inflammation loop of Inflammatory bowel disease (IBD). Aims We carried out an integrated mucosal microbiome-transcriptome analysis to elucidate associations between microbial bile-acid metabolizing function and host gene expression. Methods Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) patients were recruited prior to scheduled colonoscopy performed as part of clinical care. Only patients with non-inflamed mucosa defined as a segmental simple endoscopic score 0–2 in CD and a segmental Mayo endoscopic score of 0 in UC/IBDU were included in this analysis to minimize the effect of inflammation on gene expression. Biopsy samples were obtained from terminal ileum, ascending colon and sigmoid colon, and microbial DNA and human RNA was extracted. V4 region of 16S rRNA gene was sequenced and the relative abundance of bile acid-metabolizing genes was inferred using PICRUSt. RNA-seq was used to sequence total human RNA and a supervised transcript reduction analysis focus upon 65 genes previously associated with bile acid metabolism and IBD was utilized. Associations between microbiome clusters of orthologous groups (COGs), transcriptome, diagnosis (CD vs UC/IBDU), and biopsy site were analyzed using linear mixed-effects model with lmer4 function in R. An adjusted-p value after false discovery rate correction < 0.05 was considered significant. Results A total of 126 samples from 86 subjects were analyzed corresponding to 35 CD and 51 UC/IBDU. Mean age for the total cohort was 34.7 ± 11 years and 35 (40.6%) were females. There was a significant negative correlation between relative abundance of bacterial bsh genes (COG3049) and human RORC gene (p < 0.03). This association was independent of type of diagnosis and biopsy site. There was no association among other analyzed bacterial COGs and host genes. Conclusions Using an integrative microbiome-host transcriptome approach, our data provide new evidence linking microbial bile acid deconjugation (bsh genes) and host gene expression in the mucosal-luminal interface in quiescent IBD-affected tissue. Nuclear receptor RORC is pivotal in the differentiation and function of innate lymphoid cells and T-helper 17 cells. Modulation of this pathway by bile acids or gut bacteria involved in their metabolism could shed light on the immune role of bile acids in IBD patients. Funding Agencies CAG, CIHRNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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Impaired VLDL assembly: a novel mechanism contributing to hepatic lipid accumulation following ovariectomy and high-fat/high-cholesterol diets?

British Journal Of Nutrition ◽

10.1017/s0007114514002517 ◽

2014 ◽

Vol 112 (10) ◽

pp. 1592-1600 ◽

Cited By ~ 13

Author(s):

Isabelle Côté ◽

Natalie A. Chapados ◽

Jean-Marc Lavoie

Keyword(s):

Bile Acid ◽

Acid Metabolism ◽

Dietary Cholesterol ◽

Bile Acid Metabolism ◽

High Cholesterol ◽

High Fat ◽

Hepatic Lipid ◽

Ovx Rats ◽

Cholesterol Intake ◽

Vldl Assembly

The aim of the present study was to identify molecular mechanisms involved in liver fat and cholesterol accumulation in ovariectomised (Ovx) rats fed with high-cholesterol diets. VLDL assembly and bile acid metabolism were specifically targeted. After being either Ovx or sham-operated, the rats were fed a standard diet or a high-fat diet containing 0, 0·25 or 0·5 % cholesterol for 6 weeks. Although Ovx rats exposed to dietary cholesterol intake accumulated the greatest amount of hepatic fat and cholesterol, plasma cholesterol levels were lower (P< 0·05) in these animals than in the corresponding control rats. Accompanying this observation, ovariectomy and dietary cholesterol intake resulted in a down-regulation (P< 0·05) of the expression of genes associated with VLDL assembly, including microsomal TAG transfer protein, diacylglycerol acyltransferase 2, acyl-CoA:cholesterol acyltransferase 2 and apoB-100 as well as genes associated with bile acid metabolism including farnesoid X receptor and bile salt export pump (P< 0·01). These results indicate that high-fat/high-cholesterol diets and ovariectomy concomitantly disrupt hepatic lipid output through defects in VLDL assembly and, most probably, secretion. The results also point to a defect in hepatic bile acid secretion. The present study offers novel insights into intrahepatic lipid metabolism, which may be relevant to metabolic complications found in postmenopausal women.

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Estradiol treatment or modest exercise improves hepatic health and mitochondrial outcomes in female mice following ovariectomy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00013.2021 ◽

2021 ◽

Author(s):

Kelly N. Z. Fuller ◽

Colin S. McCoin ◽

Alex T. Von Schulze ◽

Claire J. Houchen ◽

Michael A. Choi ◽

...

Keyword(s):

Bile Acid ◽

Mitochondrial Function ◽

High Fat Diet ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

High Fat ◽

Estradiol Treatment ◽

Respiratory Capacity ◽

Female Mice ◽

Mitochondrial Respiratory

We recently reported that compared to males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice, as well as investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice (n=6 per group) were randomly assigned to sham surgery (Sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX+Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared to Sham and OVX+Est animals. Hepatic mitochondrial coupling (Basal/State 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to Sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.

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Multiple Roles of 25-Hydroxycholesterol in Lipid Metabolism, Antivirus Process, Inflammatory Response, and Cell Survival

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/8893305 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Qin Cao ◽

Zhongzhong Liu ◽

Yan Xiong ◽

Zibiao Zhong ◽

Qifa Ye

Keyword(s):

Lipid Metabolism ◽

Bile Acid ◽

Inflammatory Response ◽

Acid Metabolism ◽

Membrane Lipid ◽

Multiple Roles ◽

Bile Acid Metabolism ◽

Radical Process ◽

Underlying Mechanisms

As an essential lipid, cholesterol is of great value in keeping cell homeostasis, being the precursor of bile acid and steroid hormones, and stabilizing membrane lipid rafts. As a kind of cholesterol metabolite produced by enzymatic or radical process, oxysterols have drawn much attention in the last decades. Among which, the role of 25-hydroxycholesterol (25-HC) in cholesterol and bile acid metabolism, antivirus process, and inflammatory response has been largely disclosed. This review is aimed at revealing these functions and underlying mechanisms of 25-HC.

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Gender-divergent expression of lipid and bile acid metabolism-related genes in adult mice offspring of dams fed a high-fat diet

Journal of Biosciences ◽

10.1007/s12038-018-9750-9 ◽

2018 ◽

Vol 43 (2) ◽

pp. 329-337 ◽

Cited By ~ 6

Author(s):

Yuji Tanaka ◽

Takanori Ikeda ◽

Kazuo Yamamoto ◽

Shiori Masuda ◽

Hiroshi Ogawa ◽

...

Keyword(s):

Bile Acid ◽

High Fat Diet ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

High Fat ◽

Adult Mice

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A sulfated polysaccharide from Gracilaria Lemaneiformis regulates cholesterol and bile acid metabolism in high-fat diet mice

Food & Function ◽

10.1039/c9fo00263d ◽

2019 ◽

Vol 10 (6) ◽

pp. 3224-3236 ◽

Cited By ~ 14

Author(s):

Shiming Huang ◽

Daorui Pang ◽

Xiong Li ◽

Lijun You ◽

Zhengang Zhao ◽

...

Keyword(s):

Lipid Metabolism ◽

Bile Acid ◽

High Fat Diet ◽

Acid Metabolism ◽

Sulfated Polysaccharide ◽

Gracilaria Lemaneiformis ◽

Bile Acid Metabolism ◽

High Fat

This study aimed to evaluate the regulation of lipid metabolism and mechanism of a sulfated polysaccharide from Gracilaria Lemaneiformis (GLP).

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Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats

Journal of Nutritional Science and Vitaminology ◽

10.3177/jnsv.65.45 ◽

2019 ◽

Vol 65 (1) ◽

pp. 45-51 ◽

Cited By ~ 3

Author(s):

Reika YOSHITSUGU ◽

Keidai KIKUCHI ◽

Hitoshi IWAYA ◽

Nobuyuki FUJII ◽

Shota HORI ◽

...

Keyword(s):

Bile Acid ◽

Glucose Intolerance ◽

High Fat Diet ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

High Fat

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Effects of dietary cholesterol upon bile acid metabolism in guinea pig

Lipids ◽

10.1007/bf02532138 ◽

1974 ◽

Vol 9 (10) ◽

pp. 731-737 ◽

Cited By ~ 11

Author(s):

Heleni Lansma ◽

Rosemarie Ostwald

Keyword(s):

Bile Acid ◽

Guinea Pig ◽

Acid Metabolism ◽

Dietary Cholesterol ◽

Bile Acid Metabolism

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The influence of rosuvastatin on the gastrointestinal microbiota and host gene expression profiles

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00149.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. G488-G497 ◽

Cited By ~ 17

Author(s):

J. A. Nolan ◽

P. Skuse ◽

K. Govindarajan ◽

E. Patterson ◽

N. Konstantinidou ◽

...

Keyword(s):

Gene Expression ◽

Community Structure ◽

Bile Acid ◽

Microbial Community ◽

Gut Microbiota ◽

Acid Metabolism ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Bile Acid Metabolism ◽

Gastrointestinal Microbiota

Statins are the most widely prescribed medications worldwide for the treatment of hypercholesterolemia. They inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-R), an enzyme involved in cholesterol synthesis in higher organisms and in isoprenoid biosynthesis in some bacteria. We hypothesized that statins may influence the microbial community in the gut through either direct inhibition or indirect mechanisms involving alterations to host responses. We therefore examined the impact of rosuvastatin (RSV) on the community structure of the murine gastrointestinal microbiota. RSV was orally administered to mice and the effects on the gut microbiota, host bile acid profiles, and markers of inflammation were analyzed. RSV significantly influenced the microbial community in both the cecum and feces, causing a significant decrease in α-diversity in the cecum and resulting in a reduction of several physiologically relevant bacterial groups. RSV treatment of mice significantly affected bile acid metabolism and impacted expression of inflammatory markers known to influence microbial community structure (including RegIIIγ and Camp) in the gut. This study suggests that a commonly used statin (RSV) leads to an altered gut microbial composition in normal mice with attendant impacts on local gene expression profiles, a finding that should prompt further studies to investigate the implications of statins for gut microbiota stability and health in humans. NEW & NOTEWORTHY This work demonstrates that rosuvastatin administration in mice affects the gastrointestinal microbiota, influences bile acid metabolism, and alters transcription of genes encoding factors involved in gut homeostasis and immunity in the gastrointestinal tract.

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