Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet–fed mice

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors (including the nuclear receptor for BAs, FXR) play integral roles in regulating whole body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally-restricted Apical Sodium-dependent BA Transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high fat diet (HFD)-fed mice. Administration of this ASBTi increased fecal BA excretion and mRNA expression of BA synthesis genes in liver, and reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis, Fibroblast Growth Factor 15 (FGF15). ASBT inhibition resulted in a marked shift in hepatic BA composition, with a reduction in hydrophilic, FXR antagonistic species and an increase in FXR agonistic BAs. ASBT inhibition restored glucose tolerance, reduced hepatic triglyceride and total cholesterol concentrations, and improved NAFLD Activity Score (NAS) in HFD-fed mice. These changes were associated with reduced hepatic expression of lipid synthesis genes (including LXR target genes), and normalized expression of the central lipogenic transcription factor, Srebp1c. Accumulation of hepatic lipids and SREBP1 protein were markedly reduced in HFD-fed Asbt−/− mice, providing genetic evidence for a protective role mediated by interruption of the enterohepatic BA circulation. Taken together, these studies suggest that blocking ASBT function with a luminally-restricted inhibitor can improve both hepatic and whole body aspects of NAFLD.

Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis

“…Due to the metabolic interactions between the intestinal bile acid pool and the gut microbiota, the administration of bile acid-binding resins might readily alter the composition of intestinal microbial species, and might also have therapeutic value in the treatment of gastrointestinal cancers, particularly HCC. In addition, inhibition of enterohepatic circulation using ASBT inhibitor SC-435 improved both hepatic and systemic symptoms of nonalcoholic fatty liver disease (NAFLD) in mice fed a HFD 198 . Another ASBT inhibitor, A4250, ameliorated liver cholestasis and bile duct injury in a mouse model of PSC 199 .…”

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

“…Administration of an ASBT inhibitor in mice fed a HFD led to increased clearance of BAs in feces, increased hepatic BA synthesis, decreased FGF15, increased I-BABP, and decreased hepatic steatosis (Rao et al, 2016). Furthermore, the hepatic BA pool shifted towards FXR agonistic BAs and SREBP1c expression decreased, but the hepatic steatosis score was not significantly improved in diet-induced obese mice given a short course of an ASBT inhibitor (Rao et al, 2016). Another study using a different ASBT inhibitor, 264W94, demonstrated improved glucose tolerance and upregulation of hepatic FXR in Zucker Diabetic Fatty rats (Chen et al, 2012).…”

Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases

“…Inhibition of the IBAT (ASBT) led to increased fecal bile acid loss and altered the bile acid pool to increase bile acids, which are agonists to FXR and enhance resistance to high fat diet-induced hepatic steatosis and glucose intolerance (40). Conversely, fexaramine, an intestinal FXR agonist, also ameliorated high fat diet-induced weight gain, insulin resistance and hepatic steatosis (41).…”