title: 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.
authors.affiliation: University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: University of Perugia, Department of Medicine, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchianò
authors.affiliation: University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Biagioli
authors.affiliation: University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Santorelli
authors.affiliation: University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
authors.forename: Annibale
authors.initials: A
authors.lastname: Donini
authors.affiliation: University of Naples Federico II, Department of Pharmacy, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: University of Salerno, Department of Pharmacy, Fisciano, Salerno, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.affiliation: University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D002757:Cholanes / Q000008:administration & dosage* / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005632:Fructose / Q000009:adverse effects; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015415:Biomarkers; D002251:Carbon Tetrachloride; D002757:Cholanes; D005632:Fructose; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human