GSK3 Inhibitor Ameliorates Steatosis Through the Modulation of Mitochondrial Dysfunction in Hepatocytes of Obese Patients

Abstract

Obesity is the most important risk factor and a potential treatment target for hepatic steatosis. The maladaptation of hepatic mitochondrial flexibility plays a key role in the hepatic steatosis. Herein, we found that hepatocyte-like cells (HLCs)-derived from human adipose stem cell (hASC) of obese patients exhibited the characteristics of hepatic steatosis and accompanied with lower expression of the subunits of mitochondrial complex I and lower oxidative phosphorylation levels. The GSK3 inhibitor CHIR-99021 promoted the expression of NDUFB8, NDUFB9, the subunits of mitochondrial complex I, and the basal oxygen consumption rate of the hASC-HLCs of obese patients by upregulating the expression of the transcription factor PGC-1α involved in mitochondrial biogenesis and respiratory function. Moreover, CHIR-99021 decreased the lipid droplets size in hASC-HLCs of obese patients. The results demonstrate that GSK3 inhibition ameliorates hepatic steatosis may be elevating the mitochondrial oxidative function in adipose stem cell-derived hepatocyte-like cells from obese patients.