Hepalatide ameliorated progression of nonalcoholic steatohepatitis in mice - 19/04/20
, Jian Wu a, d, e, ⁎ Bienvenue sur EM-consulte, la référence des professionnels de santé.
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Graphical abstract |
Hepalatide blocks uptake of bile acids by NTCP receptor on hepatocytes, and leads to an increase in bile acids which act on FXR on the liver for the improvements of lipid metabolism, glucose consumption and insulin sensitivity. Increased bile acids stimulate TGR5 on muscle and adipose tissue to increase the thermogenesis and energy expenditure. BAs: bile acids; FXR: farnesoid X receptor; NTCP: sodium taurocholate cotransporting polypeptide; TG: triglyceride; TGR5: Takeda G-protein-coupled receptor 5.
Highlights |
• | Hepalatide treatment reduced body and liver weight in a murine NASH model. |
• | Hepalatide treatment attenuated hepatic steatohepatitis in mice. |
• | Hepalatide treatment improved insulin resistance in NASH mice. |
• | Hepalatide treatment blocked hepatic fibrosis progression in NASH mice. |
• | An increase in bile acids is responsible for Hepalatide’s effects as an NTCP blocker. |
Abstract |
Background |
No FDA-approved medications are available for the treatment of nonalcoholic steatohepatitis (NASH). The present study aimed to assess the effects of Hepalatide, a sodium taurocholate cotransporting polypeptide (NTCP) receptor-binding agent, on metabolic and histopathologic changes of a mouse model of NASH caused by high fat/calorie diet plus high fructose/glucose in drinking water (HFCD-HF/G) for 16 weeks.
Methods |
Male mice were randomly divided into 4 groups: controls (normal diet), HFCD-HF/G group, HFCD-HF/G plus low or high dose of Hepalatide (20 or 60 mg/kg, LH or HH, s.c. from 9 to 16 weeks).
Results |
Compared to HFCD-HF/G-fed mice, serum triglyceride and cholesterol levels in mice fed HFCD-HF/G plus LH or HH were decreased. The treatment with Hepalatide decreased serum alanine aminotransferase levels significantly. Liver histology and TUNEL staining showed that Hepalatide remarkably attenuated inflammation, hepatocellular steatosis and apoptosis. Hepalatide treatment decreased fasting blood glucose, serum insulin and HOMA insulin resistance index in the HH group. Moreover, Masson’s staining, semi-quantitative score of fibrosis, and hydroxyproline content demonstrated that Hepalatide mitigated fibrotic progression in this murine NASH model. Additionally, most components of liver and few serum bile acids were increased in mice treated with HH.
Conclusion |
Hepalatide effectively alleviated the pathological process, metabolic profile, hepatocellular steatosis and injury, insulin resistance, halted hepatic fibrotic progression in a mouse model of NASH, most likely through the increase of serum bile acids.
Le texte complet de cet article est disponible en PDF.Abbreviations : AASLD, ALT, α-SMA, AST, CCR-2, Col-Iα1, Col-Iα2, Col-IIIα1, FFA, UPLC-MS, HDL, H&E, HFCD-HF/G, HFCD-HF/G+HPLT-LD/HD, HOMA-IR, HRP, IGTT, INSR, IRS-1/2, LDL, MCP-1, NAFL, NAFLD, NAS, NASH, ORO, RT-PCR, TBA, TBIL, TC, TG, TIMP-1, TUNEL, VLDL
Keywords : Nonalcoholic steatohepatitis, Hepalatide, Bile acids, Hepatic fibrosis, Insulin resistance
Plan
Vol 126
Article 110053- juin 2020 Retour au numéro
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