Bile acid‐mediated activation of brown fat protects from alcohol‐induced steatosis and liver injury

Abstract

Background & AimsAlcohol associated liver disease (AALD) is one of the most common causes of liver injury and failure. Limited knowledge of the mechanisms underlying AALD impedes the development of efficacious therapies. Bile acid (BA) signaling was shown to participate in progression of AALD, the mechanisms of which remain poorly understood.Approach & ResultsMice were exposed to chronic‐plus‐one‐binge ethanol feeding to induce AALD. Interestingly, ethanol feeding increased expression of the thermogenesis genes downstream of TGR5 (Takeda G protein‐coupled BA receptor 5) in brown adipose tissue (BAT) of wild‐type (WT) but not TGR5 knockout (KO) mice. TGR5 deficiency significantly diminished BAT activity and energy expenditure in mice after ethanol feeding. Alcohol increased serum BA levels in mice and humans through altering BA transportation rather than increasing hepatic BA synthesis, which activated TGR5 signaling in BAT. TGR5 deficiency did not alter alcohol‐stimulated adipose lipolysis, de novo hepatic lipogenesis, or alcohol effects on hepatic β‐oxidation of free fatty acids (FFA). However, compared to ethanol‐fed WT mice, ethanol‐fed TGR5 KO mice showed less FFA β‐oxidation in BAT, leading to increased circulation and liver uptake of FFA. Importantly, in ethanol‐fed mice housed under thermoneutral conditions, TGR5‐mediated fat burning in BAT was unchanged. Finally, administration of a specific TGR5 agonist significantly activated TGR5 signaling in BAT to increase thermogenesis, reduce serum FFA level and ameliorate hepatic steatosis and injury in AALD mice.ConclusionsBA signaling plays a protective role in AALD by enhancing BAT thermogenesis and BAT crosstalk with the liver via TGR5 activation. Targeting TGR5 in BAT may be a promising approach for the treatment of AALD.