Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis

Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovascular complicationsandmortality, suggesting that treatment ofNASHmightbenefit fromcombinedapproaches that target theliver and the cardiovascular components of NASH. Using genetic and pharmacologic approaches, we show that G protein- coupledbile acid-activated receptor 1 (GPBAR1)agonism reverses liverandvasculardamage inmouse models ofNASH. NASH is associated with accelerated vascular inflammation representing an independent risk factor for development of cardiovascular diseases and cardiovascular-related mortality. GPBAR1, also known as TGR5, is a G protein-coupled receptor for secondary bile acids that reduces inflammation and promotes energy expenditure. Using genetic and pharmacologic approaches, we investigated whetherGPBAR1 agonismby 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (BAR501) reverses liver and vascular damage induced by exposure to a diet enriched in fat and fructose (HFD-F). TreatingHFD-FmicewithBAR501reversed liver injuryandpromotedthebrowningofwhiteadiposetissueinaGpbar1- dependentmanner.FeedingHFD-Fresulted invasculardamage, asshownbytheincreasedaorta intima-mediathickness and increased expression of inflammatory genes (IL-6,TNF-α, iNOS, and F4/80) and adhesion molecules (VCAM, intercellular adhesion molecule-1, andendothelial selectin) inthe aorta, while reducing the expressionof genes involvedin NO and hydrogen sulfide generation, severely altering vasomotor activities of aortic rings in an ex vivo assay. BAR501 reversed this pattern in a Gpbar1-dependent manner, highlighting a potential role for GPBAR1 agonism in treating the liverandvascular component of NASH.