CREBH promotes autophagy to ameliorate NASH by regulating Coro1a

Abstract

Dysfunctional autophagy aggravates oxidative stress and inflammation in hepatocytes and accelerates the progression of nonalcoholic steatohepatitis (NASH). Here, we demonstrated that cAMP-responsive element-binding protein H (CREBH) is a transcriptional regulator of hepatic autophagy in response to diet-induced NASH. The results showed that the upregulation of CREBH in lipid-overloaded hepatocytes improves cell damage, dysfunction of autophagic flux and associated abnormal accumulation of the autophagosome marker LC3-II and autophagic substrate p62. CREBH deficiency aggravated the dysfunctional autophagy and liver injury and even caused NASH-associated liver fibrosis. In addition, the changing trend of autolysosomes and lysosome membrane-associated protein (LAMP1) was consistent with the expression level of CREBH. This result indicated that CREBH might promote autophagic degradation by restoring the formation of autolysosomes, thereby improving the blocked autophagic flux. Moreover, we observed that CREBH inhibited the expression of Coronin 1a (Coro1a), an autophagosome-lysosome fusion-related gene, through transcriptional regulation. The overexpression of Coro1a in LO2 liver cells inhibited autophagic flux and elevated inflammatory cytokine levels upon palmitic acid (PA) stimulation. Overall, our findings provide new insights into the regulatory role of CREBH in the progression of NASH and reveal that Coro1a is a novel target gene of CREBH based on the autophagy pathway.

Keywords: Autophagy; Coronin 1a; cAMP-responsive element-binding protein H; nonalcoholic steatohepatitis.