Bile Acid–Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice

Abstract

Background & Aims Alcohol-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 the progression of AALD. However, the mechanisms remain poorly understood. Methods C57BL/6J wild-type (WT), Takeda G-protein–coupled bile acid receptor 5 (TGR5) knockout (KO) and brown adipose tissue (BAT)-specific TGR5 knockdown mice were subjected to ethanol feeding–induced AALD. Liver samples from alcoholic hepatitis patients were used to examine the BA circulation signaling. Human Embryonic Kidney Cells 293 were used for the TGR5 reporter assay. 23(S)-methyl-lithocholic acid was used as a molecular tool to confirm the regulatory functions of BAT in the AALD mouse model. Results Ethanol feeding increased the expression of the thermogenesis genes downstream of TGR5 in BAT of WT, but not TGR5 KO, mice. TGR5 deficiency significantly blocked BAT activity and energy expenditure in mice after ethanol feeding. Alcohol increased serum BA levels in mice and human beings through altering BA transportation, and the altered BAs activated TGR5 signaling to regulate metabolism. Compared with ethanol-fed WT mice, ethanol-fed TGR5 KO mice showed less free fatty acid (FFA) β-oxidation in BAT, leading to higher levels of FFA in the circulation, increased liver uptake of FFAs, and exacerbated AALD. BAT-specific TGR5 knockdown mice showed similar results with TGR5 KO mice in AALD. Agonist treatment significantly activated TGR5 signaling in BAT, increased thermogenesis, reduced serum FFA level, and ameliorated hepatic steatosis and injury in AALD mice, while these effects were lost in TGR5 KO mice. Conclusions BA signaling plays a protective role in AALD by enhancing BAT thermogenesis. Targeting TGR5 in BAT may be a promising approach for the treatment of AALD.

Browning of the white adipose tissue regulation: new insights into nutritional and metabolic relevance in health and diseases

“…In a study performed with animals under alcohol-induced hepatic steatosis or liver injury, activation of the TGR5 receptor induced improvement of clinical condition. The increase in thermogenesis in BAT promotes an increase in lipid metabolism with lower availability of circulating FFA and, consequently, lower absorption of these molecules by the liver [ 254 ]. However, if on the one hand BAs have been shown to be effective in inducing browning, on the other hand the excess of these acids is capable of promoting an antagonistic effect, such as mitochondrial dysfunction and expression of genes associated with cellular senescence in adipose cells [ 255 ].…”

Time-restricted feeding alleviates metabolic implications of circadian disruption by regulating gut hormone release and brown fat activation

“…HCA can effectively control blood sugar in the body and is intricately related to the occurrence of diabetes; 46,47 CDCA has been demonstrated to increase the activity of brown fat in humans and mice. 48,49 Therefore, these bile acids could present a functional significance with brown fat-associated metabolic regulation of tRF. The HCA and CDCA levels were restored by tRF against the CD condition in a model with brown fat removal; however, the protective reversal of metabolic syndrome was lost.…”

Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice

“…The sequence of Gm19619 was amplified by the primers Gm19619 _NotI_F (5′-aGCGGCCGCccacccaggaacagagact-3′) and Gm19619 _Esp3I_R (5′-tCGTCTCaGATCagtggcatactgtcatatatattag-3′), digested and replaced the eGFP sequence in pAAV-TBG-eGFP (Addgene #105535). The plasmid was sequenced and then used for AAV packing in 293 T cells according to the AAV protocols at the Addgene website and our previous report 39 . Eight-week-old C57BL/6 mice were received once intravenous injections of 5 × 10 11 genome copies of AAV-TBG- Gm19619 , or AAV-TBG-eGFP for control.…”