NF- B/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis

Abstract

The transcription factor nuclear factor kappa B (NF-<i>κ</i>B) is activated in hepatocytes in the pathogenesis of hepatic steatosis. However, the action mechanism of NF-<i>κ</i>B remains to be established in the hepatic steatosis. In this study, the <i>P50</i> subunit of NF-<i>κ</i>B was found to promote the hepatic steatosis through regulation of histone deacetylase 1 (HDAC1) in hepatocytes. The activity was supported by the phenotypes of <i>P50</i> knockout (<i>P50</i>-KO) mice and <i>P65</i> knockout (<i>P65</i>-KO) mice. Hepatic steatosis was reduced in the <i>P50</i>-KO mice, but not in the <i>P65</i>-KO mice. The reduction was a result of inhibition of HDAC1 activity in the <i>P50</i>-KO cells. Knockdown of <i>Hdac1</i> gene led to suppression of hepatocyte steatosis in HepG2 cells. A decrease in sterol-regulatory element binding protein 1c (SREBP1c) protein was observed in the liver of <i>P50</i>-KO mice and in cell with <i>Hdac1</i> knockdown. The decrease was associated with an increase in succinylation of SREBP1c protein. The study suggests that <i>P50</i> stabilizes HDAC1 to support the SREBP1c activity in hepatic steatosis in the pathophysiological condition. Interruption of this novel pathway in the <i>P50</i>-KO, but not the <i>P65</i>-KO mice, may account for the difference in hepatic phenotypes in the two lines of transgenic mice.