BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis

Abstract

Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs. Treatment with BAR502 caused a ≈10% reduction of b.w., increased insulin sensitivity and circulating levels of HDL, while reduced steatosis, inflammatory and fibrosis scores and liver expression of SREPB1c, FAS, PPARγ, CD36 and CYP7A1 mRNA. BAR502 increased the expression of SHP and ABCG5 in the liver and SHP, FGF15 and GLP1 in intestine. BAR502 promoted the browning of epWAT and reduced liver fibrosis induced by CCl4. In summary, BAR502, a dual FXR and GPBAR1 agonist, protects against liver damage caused by HFD by promoting the browning of adipose tissue.

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

“…After 8 wk of HFD-F administration, the mice had food withheld overnight and were then orally administered glucose (1.5 g/kg body weight) for an oral glucose tolerance test. Blood glucose concentrations were measured at 0, 15, 30, 60, 90, and 120 min after feeding or injection by using a portable glucose meter (Accu-Chek Go; Roche, Basel, Switzerland) (32). Gallbladder bile acids were measured according to a liquid chromatography-tandem mass spectrometry analysis, as described in Carino et al (32).…”

“…Blood glucose concentrations were measured at 0, 15, 30, 60, 90, and 120 min after feeding or injection by using a portable glucose meter (Accu-Chek Go; Roche, Basel, Switzerland) (32). Gallbladder bile acids were measured according to a liquid chromatography-tandem mass spectrometry analysis, as described in Carino et al (32). mice or in wild-type mice of the same genetic background (C57BL6/J), 4 wk after the start of treatment.…”

“…NASH severity (steatosis, hepatocyte ballooning, lobular inflammation, and portal inflammation) was scored in H&E-stained crosssections by using an adapted grading system of human NASH, as previously described (30). The hepatic fibrosis score was evaluated in Sirius red-stained sections, as previously described (32).…”

Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

“…Recently, a novel, non-steroidal FXR agonist, PX20606, has been shown to have anti-fi brotic and vasodilator properties and lowers portal hypertension [102]. A newly found non-bile steroidal dual ligand for FXR and GPBAR1 receptors, BAR502, reverses high-fat diet induced steatohepatitis in mice by promoting the browning of adipose tissue [103]. All of these results indicate that the FXR agonist could be an effective treatment option for NAFLD patients.…”

Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes

“…These findings highlight the complexity of BA signaling, because hepatic FXR activation with OCA would be expected to decrease BA synthesis and in turn decrease cholesterol disposal (favoring LDL accumulation) while also decreasing hepatic triglyceride‐rich lipoprotein production . It is clear that the signaling pathways involved in weight loss with OCA treatment are complex and remain incompletely understood; however, these promising results have opened the pipeline for other FXR agonists in the treatment for NAFLD …”