Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

Abstract

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that causes worldwide morbidity and mortality, yet there is still a lack of pharmacological therapies. Liver inflammation is an important contributor for disease progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH).We identified HDAC inhibitor givinostat as a potent inhibitor of macrophages inflammatory activation, and aimed to evaluate the therapeutic potential of givinostat for treatment of NASH. Daily administration of givoinostat (10mg/kg) alleviated inflammation and attenuated hepatic fibrosis in methionine-and choline-deficient diet (MCD)-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In hepatocyte givinostat reduced palmitic acid induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in fructose, palmitate, cholesterol diet (FPC) induced NASH mice. Givinostat attenuated hepatic steatosis, inflammation as well as liver injury in FPC-induced NASH. In conclusion, givinostat appears to be efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for treatment of human NASH.

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

“…S1A, second blot). We then turned to the fructose-palmitate-cholesterol (FPC) diet-induced mouse NASH model, which shows parallels to human NASH, including weight gain, insulin resistance, shared NASH-relevant signaling pathways in hepatocytes and HSCs, and fibrosis (34)(35)(36)(37)(38)(39)(40)(41). In this model, steatosis occurs by 8 weeks of diet and features of NASH, including early fibrosis, occur by 16 weeks (34).…”

Saponin monomers: Potential candidates for the treatment of type 2 diabetes mellitus and its complications

“…Chen, Yang, et al, 2019;Hu et al, 2022; Y. N. Wang, Zhao, et al, 2020), and inhibiting mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3) (Y. Fan et al, 2022) and renal tubular epithelial cell apoptosis (Ju et al, 2019). AS-IV administration significantly reduced urinary albumin excretion and urinary N-acetyl-β-D-glucosaminidase and ameliorated the renal pathologic injury in db/db mice by reducing renal dynamin-related protein, mitochondrial fission protein 1, and mitochondrial fission factor expression and by downregulating PINK1/Parkin-mediated mitophagy (X.…”