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

Abstract

Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovascular complications and mortality, suggesting that treatment of NASH might benefit from combined approaches that target the liver and the cardiovascular components of NASH. Using genetic and pharmacologic approaches, we show that G protein–coupled bile acid–activated receptor 1 (GPBAR1) agonism reverses liver and vascular damage in mouse models of NASH. 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 whether GPBAR1 agonism by 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). Treating HFD‐F mice with BAR501 reversed liver injury and promoted the browning of white adipose tissue in a Gpbar1‐dependent manner. Feeding HFD‐F resulted in vascular damage, as shown by the increased aorta intima‐media thickness and increased expression of inflammatory genes (IL‐6, TNF‐α, iNOS, and F4/80) and adhesion molecules (VCAM, intercellular adhesion molecule‐1, and endothelial selectin) in the aorta, while reducing the expression of genes involved in 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 liver and vascular component of NASH.—Carino, A., Marchianò, S., Biagioli, M., Bucci, M., Vellecco, V., Brancaleone, V., Fiorucci, C., Zampella, A., Monti, M. C., Distrutti, E., Fiorucci, S. Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. FASEB J. 33, 2809–2822 (2019). http://www.fasebj.org

Transcriptome Analysis of Dual FXR and GPBAR1 Agonism in Rodent Model of NASH Reveals Modulation of Lipid Droplets Formation

“…D12330 mod. 22,7 ME/Kg, Soest, Germany) and fructose (HFD–F) in drinking water (42 g/L) (45 mice), or normal chow diet (5 mice) for 12 weeks [20,21,23]. Food intake was estimated as the difference of weight between the offered and the remnant amount of food at 3-day intervals.…”

“…Gallbladder and fecal bile acid concentrations were measured by a liquid chromatography–tandem mass spectrometry (MS/MS), as described elsewhere [23,28,29].…”

“…Stereotyped movements during the analyzed interval, indicate the number of samples where the position of the mice is different from the position of the previous sample and equal to the position of the 2nd sample back in time. Locomotion activity indicates locomotion during the analyzed interval, i.e., distance walked in each sample where the position of the mice is different from the position of the previous sample and different of the position of the second sample back in time [23,29].…”

“…In rodents, GPBAR1 is thought to increase energy expenditure [19], and its activation attenuates insulin resistance and increases basal metabolism by inducing mitochondrial respiration uncoupling and energy expenditure in white and brown adipose tissues [20]. Furthermore, GPBAR1 exerts potent anti-inflammatory effects [21], and its agonism corrects for endothelial dysfunction in rodent models of NASH [22,23]. Because of these diverse and only partially overlapping functions, the co-activation of FXR and GPBAR1 might hold promise in the treatment of metabolic disorders, including the NASH.…”

Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential

“…Sulfated polysaccharide from Enteromorpha prolifera mimics the NaHS, a H 2 S donor, to reduce the serum triglyceride level in HFD rats through upregulating hepatic mRNA and protein expressions of CBS, a main enzyme involving in the production of H 2 S in the liver tissues [132] . G protein-coupled bile acid-activated receptor 1 agonist is demonstrated to reverse liver damage via stimulating H 2 S generation in a mouse model of steatohepatitis [133] . Garlic oil has been shown to attenuate hepatic steatosis in mice treated with ethanol via regulation of fatty acid synthase (FAS) and mitochondrial dysfunction [134] , and this agent could increase intracellular H 2 S levels in human embryonic kidney cells in the presence of cysteine or glutathione [135] .…”