Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

Boer, Jan Freark de; Schonewille, Marleen; Boesjes, Marije; Wolters, Henk; Bloks, Vincent W.; Bos, Trijnie; Dijk, Theo H. van; Jurdzinski, Angelika; Boverhof, Renze; Wolters, Justina C.; Kuivenhoven, Jan Albert; Deursen, Jan M. van; Elferink, Ronald P.J. Oude; Moschetta, Antonio; Kremoser, Claus; Verkade, Henkjan J.; Kuipers, Folkert; Groen, Albert K.

doi:10.1053/j.gastro.2016.12.037

Cited by 115 publications

(124 citation statements)

References 49 publications

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“…FGF19 and M70 treatment increased unoxidized cardiolipin species and reduced hepatic ROS, indicating conditions of reduced oxidative stress and improved mitochondrial inner membrane integrity. Furthermore, a recent study revealed that FGF19 can stimulate transintestinal cholesterol excretion through the sterol‐exporting heterodimer ABCG5/ABCG8 located in the intestine . Finally, we demonstrated that FGF19 and M70 improve glucose tolerance and enhance insulin sensitivity and energy homeostasis in the context of diet‐induced NASH.…”

Section: Discussionmentioning

confidence: 50%

Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice

Zhou

Learned

Rossi

et al. 2017

Hepatology Communications

122

104

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Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver disease for which no approved therapies are available. Despite intensive research, the cellular mechanisms that mediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulin resistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, are well‐recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as a novel mechanism contributing to NAFLD pathogenesis. Notably, NAFLD patients exhibit a deficiency in fibroblast growth factor 19 (FGF19), an endocrine hormone in the gut–liver axis that controls de novo bile acid synthesis, lipogenesis, and energy homeostasis. Using a mouse model that reproduces the clinical progression of human NAFLD, including the development of simple steatosis, nonalcoholic steatohepatitis (NASH), and advanced “burnt‐out” NASH with hepatocellular carcinoma, we demonstrate that FGF19 as well as an engineered nontumorigenic FGF19 analogue, M70, ameliorate bile acid toxicity and lipotoxicity to restore liver health. Mass spectrometry‐based lipidomics analysis of livers from mice treated with FGF19 or M70 revealed significant reductions in the levels of toxic lipid species (i.e., diacylglycerols, ceramides and free cholesterol) and an increase in levels of unoxidized cardiolipins, an important component of the inner mitochondrial membrane. Furthermore, treatment with FGF19 or M70 rapidly and profoundly reduced levels of liver enzymes, resolved the histologic features of NASH, and enhanced insulin sensitivity, energy homeostasis, and lipid metabolism. Whereas FGF19 induced hepatocellular carcinoma formation following prolonged exposure in these mice, animals expressing M70 showed no evidence of liver tumorigenesis in this model. Conclusion: We have engineered an FGF19 hormone that is capable of regulating multiple pathways to deliver antisteatotic, anti‐inflammatory, and antifibrotic activities and that represents a potentially promising therapeutic for patients with NASH. (Hepatology Communications 2017;1:1024–1042)

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Section: Discussionmentioning

confidence: 50%

Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice

Zhou

Learned

Rossi

et al. 2017

Hepatology Communications

122

104

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“…Control of the classical BA pathway is mainly regulated by the activity of cholesterol 7α‐hydroxylase (CYP7A1) and sterol 12α‐hydroxylase (CYP8B1), rate‐limiting enzymes whose transcription is inhibited by FXR‐mediated upregulation of small heterodimeric partner (NR0B2, SHP) (Lu et al, 2000), (Kong et al, 2012). In intestine, FXR activation promotes the production of fibroblast growth factor 15/19 (FGF‐19 in human), which, in turn, inhibits bile salt synthesis in the liver (Inagaki et al, 2005; Kong et al, 2012), and increases the flux of cholesterol into the intestinal lumen by activating ABCG5/ABCG8 cholesterol exporter (de Boer et al, 2017). In addition, activation of hepatic FXR modulates the expression of many hepatic genes involved in lipoprotein metabolism, including scavenger receptor class B type 1 (SR‐B1), ApoC‐II, ApoC‐III, and ApoA‐I (Lee et al, 2006; Zhang et al, 2006) and induces high‐density lipoprotein‐mediated transhepatic cholesterol efflux in mice and monkeys (Hambruch et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

et al. 2020

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Obeticholic acid (OCA) activates the farnesoid X receptor (FXR) to lower circulating total cholesterol (TC) and high density lipoprotein‐cholesterol (HDL‐C) concentrations and to stimulate fecal cholesterol excretion in mice by increasing hepatic SR‐B1 expression. Here we show that hepatic SR‐B1 depletion by an adenovirus expressing Sr‐b1 shRNA (Ad‐shSR‐B1) attenuated these beneficial effects of OCA in mice on a chow diet. The mRNA levels of ABC cholesterol transporter genes (Abca1, Abcg1, Abcg5, and Abcg8) were unchanged in the liver of hepatic SR‐B1‐depleted mice regardless of OCA treatment; however, a modest increase in Abca1, Abcg5, and Abcg8 mRNA levels was observed in the ileum of vehicle‐treated control mice and Abca1 and Abcg8 mRNA levels were increased more by OCA administration. OCA treatment of Sr‐b1 knock out (KO) mice (Sr‐b1‐/‐) fed a normal chow diet (NCD) displayed a similar lack of transhepatic cholesterol movement, as well as a modest increase in the levels of ileum cholesterol transporter expression. However, OCA treatment of Sr‐b1 KO mice fed a cholesterol‐enriched diet reduced circulating cholesterol and increased fecal cholesterol output to comparable degrees to that of wild‐type (WT) mice, and these effects were accompanied by substantial elevations of mRNA levels of Abca1, Abcg1, Abcg5, and Abcg8 in the ileum of Sr‐b1 KO mice. Our studies suggest that FXR activation stimulates intestinal cholesterol excretion and reduces diet‐induced hyperlipidemia through increased expression of ileal cholesterol transporters when hepatic SR‐B1‐mediated cholesterol movement is absent.

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“…Hepatic glycogen and G6P content was determined as described . Plasma and biliary bile acid composition were quantified using liquid chromatography‐mass spectrometry; fecal bile acid composition was quantified using capillary GC as described . The hydrophobicity index of biliary bile acids was calculated according to Heuman .…”

Section: Methodsmentioning

confidence: 99%

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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Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

Cited by 115 publications

References 49 publications

Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice

Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

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

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