Therapeutic modulation of the bile acid pool by<i>Cyp8b1</i>knockdown protects against nonalcoholic fatty liver disease in mice

Chèvre, Raphaël; Trigueros-Motos, Laia; Castaño, David; Chua, Tricia; Corlianò, Maria; Patankar, Jay V.; Sng, Lareina; Sim, Lauren; Juin, Tan Liang; Carissimo, Guillaume; Ng, Lisa F. P.; Yi, Cheryl Neo Jia; Eliathamby, Chelsea Chandani; Groen, Albert K.; Hayden, Michael R.; Singaraja, Roshni R.

doi:10.1096/fj.201701084rr

Cited by 43 publications

(30 citation statements)

References 50 publications

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“…We also show that normalization of bile composition upon hepatic ChREBP knockdown reverses reduced fecal neutral sterol excretion, consistent with the phenotype of Cyp8b1 −/− mice and with the effect of Cyp8b1 inhibition in mice. (34,36,43) However, in contrast to what was reported for Cyp8b1 −/− mice fed a high-fat diet, (34,36) fecal fatty acid and energy loss remained unaltered in the current study. In accord with our findings, Cyp8b1 heterozygous knockout mice displaying an intermediate phenotype with regard to bile acid pool composition also did not present changes in fecal calorie loss.…”

Section: Discussioncontrasting

confidence: 97%

“…Because dietary cholesterol intake (data not shown), biliary cholesterol excretion (Table ), and jejunal and ileal mRNA expression of Niemann‐Pick C1‐like 1, ATP binding cassette subfamily G member 5, ATP binding cassette subfamily G member 8, and acetyl‐CoA acetyltransferase 2 (data not shown) were similar in L‐ G6pc −/− mice and WT littermates, the reduction in neutral sterol excretion is most likely related to enhanced fractional cholesterol absorption as a consequence of the more hydrophobic bile acid pool in L‐ G6pc −/− mice. We also show that normalization of bile composition upon hepatic ChREBP knockdown reverses reduced fecal neutral sterol excretion, consistent with the phenotype of Cyp8b1 −/− mice and with the effect of Cyp8b1 inhibition in mice . However, in contrast to what was reported for Cyp8b1 −/− mice fed a high‐fat diet, fecal fatty acid and energy loss remained unaltered in the current study.…”

Section: Discussionsupporting

confidence: 89%

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Glucose‐6‐Phosphate Regulates Hepatic Bile Acid Synthesis in Mice

Hoogerland

Wolters

et al. 2019

Hepatology

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It is well established that, besides facilitating lipid absorption, bile acids act as signaling molecules that modulate glucose and lipid metabolism. Bile acid metabolism, in turn, is controlled by several nutrient-sensitive transcription factors. Altered intrahepatic glucose signaling in type 2 diabetes associates with perturbed bile acid synthesis. We aimed to characterize the regulatory role of the primary intracellular metabolite of glucose, glucose-6-phosphate (G6P), on bile acid metabolism. Hepatic gene expression patterns and bile acid composition were analyzed in mice that accumulate G6P in the liver, that is, liver-specific glucose-6-phosphatase knockout (L-G6pc−/−) mice, and mice treated with a pharmacological inhibitor of the G6P transporter. Hepatic G6P accumulation induces sterol 12α-hydroxylase (Cyp8b1) expression, which is mediated by the major glucose-sensitive transcription factor, carbohydrate response element-binding protein (ChREBP). Activation of the G6P-ChREBP-CYP8B1 axis increases the relative abundance of cholic-acid–derived bile acids and induces physiologically relevant shifts in bile composition. The G6P-ChREBP–dependent change in bile acid hydrophobicity associates with elevated plasma campesterol/cholesterol ratio and reduced fecal neutral sterol loss, compatible with enhanced intestinal cholesterol absorption. Conclusion: We report that G6P, the primary intracellular metabolite of glucose, controls hepatic bile acid synthesis. Our work identifies hepatic G6P-ChREBP-CYP8B1 signaling as a regulatory axis in control of bile acid and cholesterol metabolism.

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Section: Discussioncontrasting

confidence: 97%

Section: Discussionsupporting

confidence: 89%

Glucose‐6‐Phosphate Regulates Hepatic Bile Acid Synthesis in Mice

Hoogerland

Wolters

et al. 2019

Hepatology

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“…Cyp8b1 deficiency also increased the bile acid pool in mice, with higher T-α-MCA and T-β-MCA, which antagonize intestinal FXR. These mice also had decreased hepatic lipogenesis, improved insulin tolerance, and altered gut microbiota [8081]. Intestinal FXR plays a critical role in metabolic disease via modulation of the microbiome [82].…”

Section: Interactions Between Bile Acids and The Gut Microbiotamentioning

confidence: 99%

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

Ferrell

Chiang

2019

Diabetes Metab J

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Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic 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.

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“…Mice subjected to vertical sleeve gastrectomy, a common weight loss surgery, exhibit reduced Cyp8b1 mRNA expression as well as lower ratios of 12HBAs: non-12HBAs in circulation (22). Furthermore, siRNA against Cyp8b1 improved nonalcoholic steatohepatitis in mice (23). Thus, CYP8B1 inhibition is a potential therapeutic target for metabolic diseases.…”

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confidence: 99%

Bile acid composition regulates the manganese transporter Slc30a10 in intestine

Ahmad

Higuchi

Bertaggia

et al. 2020

Journal of Biological Chemistry

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Bile acids (BAs) comprise heterogenous amphipathic cholesterol-derived molecules that carry out physicochemical and signaling functions. A major site of BA action is the terminal ileum, where enterocytes actively reuptake BAs and express high levels of BA-sensitive nuclear receptors. BA pool size and composition are affected by changes in metabolic health, and vice versa. One of several factors that differentiate BAs is the presence of a hydroxyl group on C12 of the steroid ring. 12α-hydroxylated BAs (12HBAs) are altered in multiple disease settings, but the consequences of 12HBA abundance are incompletely understood. We employed mouse primary ileum organoids to investigate the transcriptional effects of varying 12HBA abundance in BA pools. We identified Slc30a10 as one of the top genes differentially induced by BA pools with varying 12HBA abundance. SLC30A10 is a manganese (Mn) efflux transporter critical for whole-body manganese excretion. We found that BA pools, especially those low in 12HBAs, induce cellular manganese efflux, and that Slc30a10 induction by BA pools is driven primarily by lithocholic acid signaling via the vitamin D receptor. Administration of lithocholic acid or a vitamin D receptor agonist resulted in increased Slc30a10 expression in mouse ileum epithelia. These data demonstrate a previously unknown role for BAs in intestinal control of Mn homeostasis.

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Therapeutic modulation of the bile acid pool byCyp8b1knockdown protects against nonalcoholic fatty liver disease in mice

Cited by 43 publications

References 50 publications

Glucose‐6‐Phosphate Regulates Hepatic Bile Acid Synthesis in Mice

Glucose‐6‐Phosphate Regulates Hepatic Bile Acid Synthesis in Mice

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

Bile acid composition regulates the manganese transporter Slc30a10 in intestine

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