Bile acid metabolism and signaling, the microbiota, and metabolic disease
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
Jingwei Cai
Bipin Rimal
Changtao Jiang
John Y L Chiang
Andrew D Patterson
Pharmacol Ther
. 2022 Sep;237:108238. doi: 10.1016/j.pharmthera.2022.108238. Epub 2022 Jul 2.
English
Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.
Mice overexpressing or deficient in hepatocyte miR-34a and control mice were fed a diet enriched in fats, cholesterol, and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo. The effect of miR-34a on the development, progression, and reversal of NAFLD was determined.
Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice and patients with non-alcoholic steatohepatitis (NASH), yet hepatocyte miR-34a's role in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.
Xu Y; Zhu Y; Hu S; Pan X; Bawa FC; Wang HH; Wang DQ; Yin L; Zhang Y
Molecular Metabolism
2021
2021-05-15
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Journal Article
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Hepatocyte nuclear factor 4α prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling.
steatohepatitis; apoptosis; bile acid; HNF4α; lipolysis; P53
Hepatocyte nuclear factor 4α (HNF4α) is highly enriched in the liver, but its role in the progression of liver steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) has not been elucidated. In this study, we investigated the effect of gain or loss of hepatocyte HNF4α function on the development and progression of non-alcoholic fatty liver disease (NAFLD) in mice. Over-expression of human HNF4α protected against high fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis whereas loss of hepatocyte Hnf4α had opposite effects. HNF4α prevented hepatic triglyceride accumulation by promoting hepatic triglyceride lipolysis, fatty acid oxidation and VLDL secretion. Furthermore, HNF4α suppressed the progression of NAFL to NASH. Over-expression of human HNF4α inhibited HFCF diet-induced steatohepatitis in control mice but not in hepatocyte-specific p53(-/-) mice. In HFCF diet-fed mice lacking hepatic Hnf4α, recapitulation of hepatic expression of HNF4α targets cholesterol 7α-hydroxylase and sterol 12α-hydroxylase normalized hepatic triglyceride levels and attenuated steatohepatitis. CONCLUSIONS: The current study indicates that hepatocyte HNF4α protects against diet-induced development and progression of NAFLD by coordinating the regulation of lipolytic, p53 and bile acid signaling pathways. Targeting hepatic HNF4α may be useful for treatment of NASH.
Xu Y;Zhu Y;Hu S;Xu Y;Stroup D;Pan X;Bawa FC;Chen S;Gopoju R;Yin Liya;Zhang Y
Hepatology
2020
2020-10-23
journalArticle
<a href="http://doi.org/10.1002/hep.31604" target="_blank" rel="noreferrer noopener">10.1002/hep.31604</a>
Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease.
alcoholic liver disease (ALD); bacterial translocation; Bile acid; binding protein; farnesoid X receptor (FXR); farnesoid-x-receptor; fatty liver; glucagon-like peptide-1; growth-factor 19; gut microbiota; microbiota; molecular-cloning; non-alcoholic steatohepatitis (NASH); non-alcoholic steatohepatitis (NASH); nuclear receptor; solute transporter-alpha
Bile acids are synthesized from cholesterol only in hepatocytes. Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine. Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor TGR5. FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis. In addition, bile acid-activated cellular signaling pathways regulate metabolic homeostasis, immunity, and cell proliferation in various metabolically active organs. In the small and large intestine, gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects. In turn, bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity. Currently, bile acid-based therapies including systemic and intestine-restricted FXR agonists, TGR5 agonists, fibroblast growth factor 19 analogue, intestine FXR antagonists, and intestine apical sodium-bile acid transporter (ASBT) inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis (NASH). These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest. More recently, human and experimental alcoholic liver disease (ALD) has been associated with disrupted bile acid homeostasis. In additional, new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
Li Tiangang; Chiang John Y L
Hepatobiliary surgery and nutrition
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.21037/hbsn.2019.09.03" target="_blank" rel="noreferrer noopener">10.21037/hbsn.2019.09.03</a>
Transcriptional suppression of cytochrome P450 genes by endogenous and exogenous chemicals
bile acid; cholesterol 7 alpha-hydroxylase; cyp2c11 gene; cyp7a1 transcription; down-regulation; messenger-rna; nuclear receptor; Pharmacology & Pharmacy; polycyclic aromatic-hydrocarbons; pregnane X receptor; rat-liver
This article is an invited report of a symposium sponsored by the Division for Drug Metabolism of the American Society for Pharmacology and Experimental Therapeutics held at Experimental Biology 2003 in San Diego, California, April 11 - 15, 2003. Several members of the cytochrome P450 (P450) superfamily are induced after exposure to a variety of chemical signals, and we have gained considerable mechanistic insight into these processes over the past four decades. In addition, the expression of many P450s is suppressed in response to various endogenous and exogenous chemicals; however, relatively little is known about the molecular mechanisms involved. The goal of this symposium was to critically examine our current understanding of molecular mechanisms involved in transcriptional suppression of CYP genes by endogenous and exogenous chemicals. Specific examples were drawn from the following chemical categories: polycyclic and halogenated aromatic hydrocarbon environmental toxicants, inflammatory mediators, the endogenous sterol dehydroepiandrosterone and peroxisome proliferators, and bile acids. Multiple molecular mechanisms are involved in transcriptional suppression, and these processes often involve rather complex cascades of transcription factors and other regulatory proteins. Mechanistic studies of CYP gene suppression can enhance our understanding of how organisms respond to xenobiotics as well as to perturbations in endogenous chemicals involved in maintaining homeostasis.
Riddick D S; Lee C; Bhathena A; Timsit Y E; Cheng P Y; Morgan E T; Prough R A; Ripp S L; Miller K K M; Jahan A; Chiang J Y L
Drug Metabolism and Disposition
2004
2004-04
Journal Article
<a href="http://doi.org/10.1124/dmd.32.4.367" target="_blank" rel="noreferrer noopener">10.1124/dmd.32.4.367</a>
Hep G2 cells: A model for studies on regulation of human cholesterol 7 alpha-hydroxylase at the molecular level
bile acid; bile-acid synthesis; biosynthesis; density-lipoprotein receptors; expression; Gastroenterology & Hepatology; hepatocytes; line; liver; messenger-rna; metabolism; monolayer-cultures; Physiology; primary; rat; transcriptional activity
The present study examines the feedback control governing human cholesterol 7 alpha-hydroxylase mRNA expression in the human hepatoblastoma cell line, Hep G2. Glycochenodeoxycholate (GCDC) and glycodeoxycholate, hydrophobic bile salts, decreased cholesterol 7 alpha-hydroxylase mRNA levels and bile acid synthesis in a concentration-dependent (76 +/- 8%, P < 0.001, and 48 +/- 3%, P < 0.01, respectively) and time-dependent manner. Cholesterol 7 alpha-hydroxylase mRNA levels were repressed with a half-maximal inhibitory concentration of < 12.5 mu M by GCDC and a half-life of 30 min by 100 mu M of the bile acid. The addition of actinomycin D (10 mu g/ml) alone or in combination with GCDC (100 mu M) led to similar concentration- and time-dependent suppression of cholesterol 7 alpha-hydroxylase mRNA. Glycocholate (100 mu M), not internalized based on lack of uptake of a fluorescent cholate analogue, had no effect on cholesterol 7 alpha-hydroxylase mRNA or total bile acid synthesis. In cultures transfected with a rat cholesterol 7 alpha-hydroxylase promoter construct, reporter gene activity was decreased (31%, P < 0.01) by GCDC (100 alpha M). Hep G2 cells maintain the intracellular machinery to express and rapidly regulate human cholesterol 7 alpha-hydroxylase by hydrophobic bile acids. These data suggest that Hep G2 cells will support functional studies of the human cholesterol 7 alpha-hydroxylase gene.
Pandak W M; Stravitz R T; Lucas V; Heuman D M; Chiang J Y L
American Journal of Physiology-Gastrointestinal and Liver Physiology
1996
1996-03
Journal Article
<a href="http://doi.org/10.1152/ajpgi.1996.270.3.g401" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.1996.270.3.g401</a>
Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7 alpha-hydroxylase gene
acid receptor; bile acid; bile-acid synthesis; Biochemistry & Molecular Biology; Biophysics; cholesterol metabolism; feedback-regulation; fxr; liver; natural product; nuclear receptor; nuclear receptors; pregnane X receptor; transport
Bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces bile salt export pump (BSEP) but inhibits cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription in the liver. Guggulsterone, a plant sterol that lowers serum cholesterol, has been shown to antagonize FXR activated genes. Transient transfection assay of a human BSEP/luciferase reporter in HepG2 cells transfected with FXR reveals that guggulsterone strongly antagonizes bile acid induction of the BSEP gene. On the other hand, guggulsterone has no effect on FXR inhibition of the CYP7A1 gene, but strongly inhibits the human CYP7A1 gene by activation of pregnane X receptor (PXR). These results suggest that guggulsterone inhibits bile acid secretion from hepatocytes into bile and activates PXR to inhibit bile acid synthesis in the liver. Reduced conversion of cholesterol and bile acid excretion may lead to an increase of hepatic cholesterol and decrease of intestinal cholesterol absorption, and results in lowering serum cholesterol. (C) 2003 Elsevier Science (USA). All rights reserved.
Owsley E; Chiang J Y L
Biochemical and Biophysical Research Communications
2003
2003-04
Journal Article
<a href="http://doi.org/10.1016/s0006-291x(03)00551-5" target="_blank" rel="noreferrer noopener">10.1016/s0006-291x(03)00551-5</a>
Orphan nuclear receptor oestrogen-related receptor gamma (ERRgamma) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression.
Animals; bile acid; Bile Acids and Salts/metabolism; Cannabinoid; cannabinoid receptors; CB1/agonists/genetics/*metabolism; Cells; Cholesterol 7-alpha-Hydroxylase/*biosynthesis/genetics; cholesterol 7alpha-hydroxylase (CYP7A1); Cultured; Cytoplasmic and Nuclear/metabolism; Drug Inverse Agonism; Estrogen/genetics/*metabolism; Ethanol/pharmacology; Gene Expression; Genetic; Glycerides/pharmacology; GSK5182; HEK293 Cells; Hepatocytes/metabolism; Humans; Inbred C57BL; Knockout; Liver/*metabolism; Mice; oestrogen-related receptor gamma (ERRgamma); orphan nuclear receptor; Promoter Regions; Rats; Receptor; Receptors; small heterodimer partner (SHP); Sprague-Dawley; Transcription
Bile acids are primarily synthesized from cholesterol in the liver and have important roles in dietary lipid absorption and cholesterol homoeostasis. Detailed roles of the orphan nuclear receptors regulating cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, have not yet been fully elucidated. In the present study, we report that oestrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERRgamma-mediated transcription of the CYP7A1 gene. Overexpression of ERRgamma increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERRgamma attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERRgamma-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERRgamma and thus regulated CYP7A1 expression. Overexpression of ERRgamma led to increased bile acid levels, whereas an inverse agonist of ERRgamma, GSK5182, reduced CYP7A1 expression and bile acid synthesis. Finally, GSK5182 significantly reduced hepatic CB1 receptor-mediated induction of CYP7A1 expression and bile acid synthesis in alcohol-treated mice. These results provide the molecular mechanism linking ERRgamma and bile acid metabolism.
Zhang Yaochen; Kim Don-Kyu; Lee Ji-Min; Park Seung Bum; Jeong Won-Il; Kim Seong Heon; Lee In-Kyu; Lee Chul-Ho; Chiang John Y L; Choi Hueng-Sik
The Biochemical journal
2015
2015-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1042/BJ20141494" target="_blank" rel="noreferrer noopener">10.1042/BJ20141494</a>