Abstract
Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis (NASH), and improve the metabolic aspects of the disease. Potential disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased the total amount of bile acid in feces. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition. Non-alcoholic fatty liver disease activity score (NAS) was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1β, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of NASH pathophysiology.
Highlights
Total fecal bile acid levels were similar for the chow and high-fat diet (HFD) control groups, and remained similar to baseline levels throughout the study (Fig 4A)
By week 24, plasma cholesterol, insulin, and alanine aminotransferase (ALT) levels were all significantly lower in the 30 mg/kg dose group than in the HFD control group. These findings indicate that volixibat had beneficial effects on multiple aspects of non-alcoholic steatohepatitis (NASH) pathology in this translational diet-induced NASH mouse model.[46,47,48]
The observed effects are consistent with the mechanism of action of volixibat, indicating local inhibition of the apical sodium-dependent bile acid transporter (ASBT) in the intestinal lumen and the subsequent interruption of enterohepatic bile acid reabsorption
Summary
Over the past two decades, rising rates of obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome have been accompanied by an increasing prevalence of non-alcoholic steatohepatitis (NASH).[1, 2] NASH is a severe and often progressive form of non-alcoholic fatty
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