Interactive Relationships between Intestinal Flora and Bile Acids
The digestive tract is replete with complex and diverse microbial communities that are important for the regulation of multiple pathophysiological processes in humans and animals, particularly those involved in the maintenance of intestinal homeostasis, immunity, inflammation, and tumorigenesis. The diversity of bile acids is a result of the joint efforts of host and intestinal microflora. There is a bidirectional relationship between the microbial community of the intestinal tract and bile acids in that, while the microbial flora tightly modulates the metabolism and synthesis of bile acids, the bile acid pool and composition affect the diversity and the homeostasis of the intestinal flora. Homeostatic imbalances of bile acid and intestinal flora systems may lead to the development of a variety of diseases, such as inflammatory bowel disease (IBD), colorectal cancer (CRC), hepatocellular carcinoma (HCC), type 2 diabetes (T2DM), and polycystic ovary syndrome (PCOS). The interactions between bile acids and intestinal flora may be (in)directly involved in the pathogenesis of these diseases.
Xiaohua Guo
Edozie Samuel Okpara
Wanting Hu
Chuyun Yan
Yu Wang
Qionglin Liang
John Y L Chiang
Shuxin Han
Int J Mol Sci
. 2022 Jul 28;23(15):8343. doi: 10.3390/ijms23158343.
2022
English
Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.
miR-34a; NAFLD; Lipogenesis; bile acids; Bile acids; lipid absorption; lipogenesis; Lipid absorption
Objectives: Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice, and patients with non-alcoholic steatohepatitis (NASH), yet the role of hepatocyte miR-34a in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.; Methods: Mice over-expressing or deficient in hepatocyte miR-34a and their 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 or reversal of NAFLD was determined.; Results: Hepatocyte-specific expression of miR-34a aggravated HFCF diet-induced NAFLD. In contrast, germline or adult-onset loss of hepatocyte miR-34a attenuated the development and progression of NAFLD. In addition, pharmacological inhibition of miR-34a reversed HFCF diet-induced steatohepatitis. Mechanistically, hepatocyte miR-34a regulated the development and progression of NAFLD by inducing lipid absorption, lipogenesis, inflammation and apoptosis, and inhibiting fatty acid oxidation.; Conclusions: Hepatocyte miR-34a is an important regulator in the development and progression of NAFLD. MiR-34a may be a useful target for treating NAFLD. (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Xu Y; Zhu Y; Hu S; Pan X; Bawa FC; Wang HH; Wang DQ; Yin L; Zhang Y
Molecular Metabolism
2021
2021-04-27
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/10.1016/j.molmet.2021.101244" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2021.101244</a>
Regulation of the hamster cholesterol 7 alpha-hydroxylase gene (CYP7A): Prevalence of negative over positive transcriptional control
Biophysics; down-regulation; Biochemistry & Molecular Biology; hmg-coa reductase; messenger-rna levels; Bile acids; protein-kinase-c; cultures; primary; thyroid-hormone; rat hepatocytes; hormonal-regulation; hypophysectomized rats
Cholesterol 7 alpha-hydroxylase plays a crucial role in cholesterol homeostasis. We investigated the regulation of this enzyme in the hamster, a suitable animal model for studying cholesterol metabolism. DNase I hypersensitivity assay revealed the presence of a hypersensitive region in the proximal promoter. Both negative (bile acids, phorbol esters and insulin) and positive (glucocorticoid hormones) effects were mediated through sequences in the region 318 bp upstream of the ATG codon. All-trans-retinoic acid, cAMP, and LDL did not affect transcriptional activity. These findings show that the hamster cholesterol 7 alpha-hydroxylase gene undergoes a predominant negative regulation, as opposed to the rat CYP7A homologous gene. (C) 1996 Academic Press, Inc.
DeFabiani E; Crestani M; Marrapodi M; Pinelli A; Chiang J Y L; Galli G
Biochemical and Biophysical Research Communications
1996
1996-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1006/bbrc.1996.1412" target="_blank" rel="noreferrer noopener">10.1006/bbrc.1996.1412</a>
Regulation of cholesterol 7 alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXR alpha)
bile acid synthesis; expression; Signaling; dietary-cholesterol; Bile acids; pathway; nuclear receptor; nuclear receptors; promoter; Genetics & Heredity; x-receptor; cytochrome P450; gene regulation; reverse cholesterol transport; hepg2 cells; coup-tfii; ligands
The cholesterol 7 alpha -hydroxylase gene (CYP7A1) plays an important role in regulation of bile acid biosynthesis and cholesterol homeostasis. Oxysterol receptor, LXR, stimulates, whereas the bile acid receptor, FXR, inhibits CYP7A1 transcription. The goal of this study was to investigate the role of LXR alpha on the regulation of rat, human and hamster CYP7A1 transcription in its native promoter and cellular context. Cotransfection with LXR alpha and RXR alpha expression plasmids strongly stimulated rat CYP7A1/luciferase reporter activity in HepG2 cells and oxysterol was not required. However, LXR alpha had much less effect on hamster and no significant effect on human CYP7A1 promoter activity in HepG2 cells. In Chinese hamster ovary cells, cotransfection with LXR alpha stimulated reporter activity by less than 2-fold and addition of 22(R)-hydroxycholesterol caused a small but significant stimulation of rat, human and hamster CYP7A1 promoter activity. At least two direct repeats of AGGTCA-like sequences with 4-base spacing (DR4) and five-base spacing (DR5), in previously identified bile acid response elements of the rat CYP7A1 were able to bind LXR alpha /RXR alpha and confer LXR alpha stimulation. However, LXR alpha did not bind to the corresponding sequences of the human gene and bound weakly to hamster and mouse DR4 sequences. Therefore, rats and mice have the unusual capacity to convert cholesterol to bile acids by LXR alpha -mediated stimulation of CYP7A1 transcription, whereas other species do not respond to cholesterol and develop hypercholesterolemia on a diet high in cholesterol. (C) 2001 Elsevier Science B.V. All rights reserved.
Chiang J Y L; Kimmel R; Stroup D
Gene
2001
2001-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/s0378-1119(00)00518-7" target="_blank" rel="noreferrer noopener">10.1016/s0378-1119(00)00518-7</a>
Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice
metabolomics; 1; Biochemistry & Molecular Biology; disease; expression; absorption; permeability; Bile acids; bile-acid; cytochrome-p450 3a4; vitamin D receptor; vitamin D receptor; 25-dihydroxyvitamin d-3
Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr(Delta IEpC)) have abnormal body size, colon structure, and imbalance of bile acid metabolism. Lithocholic acid (LCA), a secondary bile acid that activates VDR, is among the most toxic of the bile acids that when overaccumulated in the liver causes hepatotoxicity. Because cytochrome P450 3A4 (CYP3A4) is a target gene of VDR-involved bile acid metabolism, the role of CYP3A4 in VDR biology and bile acid metabolism was investigated. The CYP3A4 gene was inserted into Vdr(Delta IEpC) mice to produce the Vdr(Delta IEpC)/3A4 line. LCA was administered to control, transgenic-CYP3A4, Vdr(Delta IEpC), and Vdr(Delta IEpC)/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr(Delta IEpC) mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr(Delta IEpC)/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine.(jlr) This study reveals that intestinal CYP3A4 protects against LCA hepatotoxicity.
Cheng J; Fang Z Z; Kim J H; Krausz K W; Tanaka N; Chiang J Y L; Gonzalez F J
Journal of Lipid Research
2014
2014-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1194/jlr.M044420" target="_blank" rel="noreferrer noopener">10.1194/jlr.M044420</a>
Hepatic Cannabinoid Receptor Type 1 Mediates Alcohol-Induced Regulation of Bile Acid Enzyme Genes Expression Via CREBH
metabolism; Ohio; mice; Signaling; Signal transduction; liver; Homeostasis; transcription factor; Genes; exposure; Acids; er stress; endoplasmic-reticulum stress; Science & Technology - Other Topics; insulin-resistance; cholesterol 7-alpha-hydroxylase; human hepatocytes; Rodents; Bile acids; alcohol; element-binding protein; gene-expression; endocannabinoid system; bound; cb1 receptors; leptin resistance; Liver diseases; Diabetes mellitus; insulin-resistance; insulin; Fatty liver; hepatocytes; Sciences: Comprehensive Works; Alcohols; Bile; activation; Damage prevention; Deregulation; Muridae; Regulatory mechanisms (biology); RNA extraction; Synthesis
Bile acids concentration in liver is tightly regulated to prevent cell damage. Previous studies have demonstrated that deregulation of bile acid homeostasis can lead to cholestatic liver disease. Recently, we have shown that ER-bound transcription factor Crebh is a downstream effector of hepatic Cb1r signaling pathway. In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process. We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo alongwith significant increase in Crebh gene expression and activation. Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis. Overexpression of Crebh increased the expression of key bile acid synthesis enzyme genes via direct binding of Crebh to their promoters, whereas Cb1r knockout and Crebh-knockdown mice were protected against alcohol-induced perturbation of bile acid homeostasis. Interestingly, insulin treatment protected against Cb1r-mediated Crebh-induced disruption of bile acid homeostasis. Furthermore, Crebh expression and activation was found to be markedly increased in insulin resistance conditions and Crebh knockdown in diabetic mice model (db/db) significantly reversed alcohol-induced disruption of bile acid homeostasis. Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis.
Chanda D; Kim Y H; Li T; Misra J; Kim D K; Kim J R; Kwon J; Jeong W I; Ahn S H; Park T S; Koo S H; Chiang J Y L; Lee C H; Choi H S
PLOS ONE
2013
2013-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1371/journal.pone.0068845" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0068845</a>
Orphan receptors chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and retinoid X receptor (RXR) activate and bind the rat cholesterol 7 alpha-hydroxylase gene (CYP7A)
arp-1; bile acids; Biochemistry & Molecular Biology; cloning; expression; liver; messenger-rna; regulatory protein-1; response elements; superfamily; thyroid-hormone
The cholesterol 7 alpha-hydroxylase gene (CYP7A) is transcriptionally regulated by a number of factors, including hormones, bile acids, and diurnal rhythm. Previous studies have identified a region from nucleotides (nt) -74 to -55 of the rat CYP7A promoter that enhanced bile acid repression of the SV40 early promoter, as assayed with a luciferase reporter gene in transiently transfected HepG2 cells. The rat CYP7A promoter/reporter activity was strongly stimulated by cotransfection with an expression plasmid encoding the nuclear hormone receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) in a dose-dependent manner. Site-directed mutagenesis in the region of nt -74 to -55 altered this stimulation. Recombinant COUP-TFII expressed in HepG2 or COS-1 cells were found to bind to nt -74 -55 and nt -149 -128 probes by electrophoretic mobility shift assay (EMSA) and by supershifting the corresponding band with COUP-TFII-specific antibodies. The region of nt -176 -117 was previously mapped as a retinoic acid response region and was found to bind retinoid X receptor (RXR). EMSA supershift assays of wild-type and mutant oligomers using antibody against RXR revealed that the sequences between nt -145 and -134 were important for RXR binding. We conclude that COUP-TFII stimulates the transcriptional activity of the rat CYP7A promoter by binding to the sequences between nt -74 to -54 and nt -149 to -128. RXR may stimulate CYP7A gene transcription by binding to a direct repeat of the hormone response element separated by one nucleotide located at nt -146 -134.
Stroup D; Crestani M; Chiang J Y L
Journal of Biological Chemistry
1997
1997-04
Journal Article
n/a
HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7 alpha-hydroxylase gene (CYP7A1)
bile-acid synthesis; bile acids; Biochemistry & Molecular Biology; chicken ovalbumin; cholesterol metabolism; dna-binding; hepatocyte nuclear factor 4; hepatocyte nuclear factor 4; hormone-receptor superfamily; messenger-rna; orphan receptors; promoter; receptors; response elements; retinoic acid; thyroid-hormone; transcriptional regulation; upstream promoter transcription factor II
The gene for cholesterol 7 alpha-hydroxylase (CYP7A1) contains a sequence at nt -149 to -118 that was found to play a large role in determining the overall transcriptional activity and regulation of the promoter. Hepatocyte nuclear factor 4 (HNF4) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) synergistically activate transcription of the CYP7A1 promoter, Transactivation of CYP7A1 by HNF4 in the human hepatoma cell line, HepG2, was enhanced by cotransfection with COUP-TFII or the basal transcription element binding protein (BTEB), HNF4 prepared from rat liver nuclear extracts bound to oligomers homologous to the nt -146 to -134 sequences in electrophoretic mobility shift assays (EMSA), which corresponded to a conserved region containing a direct repeat of hormone response elements spaced by one nucleotide (DR1), The sequences surrounding this DR1 were found to be essential for the HNF4 transactivation. In vitro-translated COUP-TFII was found to bind the adjacent sequences from nt -139 to -128 (DRO), but COUP-TFII interacted with this region at a much lower affinity than to the COUP-TFII-site at nt -72 to -57 (DR4), Mutations at nt -139 to -128 or nt -72 to -57 reduced the COUP-TFII and HNF4 synergy; however, these COUP-TFII-binding sequences were not absolutely required for the cooperative effect of HNF4 and COUP-TFII on transactivation. These results indicated that the observed transactivation was the result of protein/protein interactions facilitated by the juxtaposition of the binding elements.
Stroup D; Chiang J Y L
Journal of Lipid Research
2000
2000-01
Journal Article
n/a
BILE-ACID SYNTHESIS .6. REGULATION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE BY TAUROCHOLATE AND MEVALONATE
3-hydroxy-3-methylglutaryl; 7-alpha-hydroxylase; bile acids; Biochemistry & Molecular Biology; biosynthesis; circadian-rhythm; cloning; coenzyme; enzyme; hepatocytes; hmg-coa reductase; liver; messenger-rna; rat-liver microsomes; reductase; substrate
Taurocholate, a relatively hydrophobic bile salt, is a potent down-regulator of HMG-CoA reductase and cholesterol 7-alpha-hydroxylase (C7-alpha-H), the rate-determining enzymes of the cholesterol and bile acid biosynthetic pathways, respectively. Inhibition of cholesterol synthesis with a bolus dose of mevinolin (lovastatin) a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, profoundly decreases the specific activity of cholesterol 7-alpha-hydroxylase and rate of bile acid synthesis in rats with complete biliary diversion. It is therefore conceivable that taurocholate may suppress cholesterol 7-alpha-hydroxylase primarily by down-regulating the activity of HMG-CoA reductase. To test this hypothesis, taurocholate was coinfused simultaneously to rats with chronic bile fistula with mevalonate (administered as mevalonolactone), an intermediate in the cholesterol biosynthetic pathway. Mevalonolactone was administered to provide a constant supply of newly synthesized cholesterol to cholesterol 7-alpha-hydroxylase, in order to overcome any inhibitory effect of taurocholate on HMG-Coa reductase. Infusions were started 72 h after biliary diversion, and carried out for an additional 48 h. Complete biliary diversion resulted in an increase in C7-alpha-H specific activity (510%), protein mass (550%), steady-state mRNA levels (1430%), and transcriptional activities (330%) as compared to control rats with intact enterohepatic circulations. When rats with biliary diversion were infused intraduodenally with taurocholate, the specific activities of HMG-CoA reductase and cholesterol 7-alpha-hydroxylase activities decreased by 75% (P < 0.001) and 73% (P < 0.001), respectively. Cholesterol 7-alpha-hydroxylase mass, mRNA, and transcriptional activity decreased after intraduodenal infusion of taurocholate to levels similar to those of rats with an intact enterohepatic circulation. The combination of constant infusion of mevalonate and taurocholate failed to reverse the inhibitory effects of taurocholate on cholesterol 7-alpha-hydroxylase activity, mRNA levels, and in vitro transcriptional rates. These data provide evidence that taurocholate represses cholesterol 7-alpha-hydroxylase at the level of gene transcription, and not via down-regulation of HMG-CoA reductase. Infusion of mevalonate alone to biliary diverted rats did not alter cholesterol 7-alpha-hydroxylase activity or mRNA levels, while leading to a 57% decrease in C7-alpha-H gene transcription. This latter finding suggests that mevalonate or its metabolites may be capable of stabilizing C7-alpha-H mRNA levels while down-regulating transcriptional activity.
Pandak W M; Vlahcevic Z R; Chiang J Y L; Heuman D M; Hylemon P B
Journal of Lipid Research
1992
1992-05
Journal Article
n/a
Mechanisms of cholesterol and sterol regulatory element binding protein regulation of the sterol 12 alpha-hydroxylase gene (CYP8B1)
bile acids; bile-acid metabolism; Biochemistry & Molecular Biology; Biophysics; cholesterol; CYP8B1; gene regulation; liver; mice; mouse; pathway; promoter; rat; receptor lxr-alpha; SREBP; srebps; suppresses
Sterol 12alpha-hydroxylase (CYP8B1) is an obligatory enzyme for the synthesis of cholic acid and regulation of liver bile acid synthesis and intestine cholesterol absorption. The present study evaluates the roles for sterol regulatory element binding proteins (SREBPs) in the regulation of the CYP8B1 gene. Cholesterol feeding of mice and rats decreased the activity of CYP8B1, contrary to the up-regulation of cholesterol 7alpha-hydroxylase (CYP7A1). Cholesterol feeding also reduced mRNA levels for SREBP-1 but not for SREBP-2 in rat livers. Cholesterol and 25-hydroxycholesterol decreased the CYP8B1/luciferase reporter activity. Co-transfection of SREBP-1a and -1c stimulated CYP8B1 promoter activity, while SREBP-2 did not have any effects. Electrophoretic mobility shift assay and mutagenesis analyses identified several functional sterol regulatory elements (SRE) and E-box motifs in the rat CYP8B1 promoter. Our results indicate that SREBP-1a and -1c enhance transcription of the CYP8B1 gene through binding to SRE. Cholesterol loading reduces SREBP-1 mRNA expression in addition to reducing functional SREBP-1 protein, and results in decreasing CYP8B1 gene transcription. (C) 2004 Elsevier Inc. All rights reserved.
Yang Y Z; Eggertsen G; Gafvels M; Andersson U; Einarsson C; Bjorkhem I; Chiang J Y L
Biochemical and Biophysical Research Communications
2004
2004-08
Journal Article
<a href="http://doi.org/10.1016/j.bbrc.2004.06.069" target="_blank" rel="noreferrer noopener">10.1016/j.bbrc.2004.06.069</a>
Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation
7alpha-hydroxy-4-cholesten-3-one; aminotransferase; aspartate-aminotransferase isozymes; bile acids; Cyp7a1; FGF19; fibroblast-growth-factor; fibroblast-growth-factor; hepatocellular carcinoma; identification; induced liver-injury; Klotho beta; lipophilicity; liver injury; mitigation; nuclear receptor; serum; sinusoidal endothelial-cells; suppression; tgr5; Toxicology
The FGF19- fibroblast growth factor receptor (FGFR4)-beta Klotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1., elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.
Schadt H S; Wolf A; Mahl J A; Wuersch K; Couttet P; Schwald M; Fischer A; Lienard M; Emotte C; Teng C H; Skuba E; Richardson T A; Manenti L; Weiss A; Porta D G; Fairhurst R A; Kullak-Ublick G A; Chibout S D; Pognan F; Kluwe W; Kinyamu-Akunda J
Toxicological Sciences
2018
2018-05
Journal Article
<a href="http://doi.org/10.1093/toxsci/kfy031" target="_blank" rel="noreferrer noopener">10.1093/toxsci/kfy031</a>
Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets.
BILE acids; Bile acids and salts; cholesterol 7-alpha-hydroxylase; Cytoplasmic and Nuclear; Endocrinology & Metabolism; FARNESOID X receptor; farnesoid-x-receptor; FATTY liver; fatty liver-disease; G protein coupled receptors; G-protein-coupled; Gastrointestinal microbiome; growth-factor 19; gut microbiota; hepatic steatosis; improves insulin sensitivity; liver disease; metabolic; Non-alcoholic fatty; Non-alcoholic Fatty Liver Disease; nuclear; receptor; Receptors; serum fgf21 levels; syndrome
Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and nonalcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]
Ferrell Jessica M; Chiang John Y L
Diabetes & Metabolism Journal
2019
2019-06
<a href="http://doi.org/10.4093/dmj.2019.0043" target="_blank" rel="noreferrer noopener">10.4093/dmj.2019.0043</a>
A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects.
BILE acids; HOMEOSTASIS; HYPOGLYCEMIC agents; INSULIN resistance; LABORATORY mice; LECITHIN; TRIGLYCERIDES
Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis. [ABSTRACT FROM AUTHOR]
Lee Jae Man; Lee Yoon-Kwang; Mamrosh Jennifer L; Busby Scott A; Griffin Patrick R; Pathak Manish C; Ortlund Eric A; Moore David D
Nature
2011
2011-06-23
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/10.1038/nature10111" target="_blank" rel="noreferrer noopener">10.1038/nature10111</a>