microRNA-378b regulates ethanol-induced hepatic steatosis by targeting CaMKK2 to mediate lipid metabolism

Abstract

Alcoholic liver disease (ALD) has seriously harmed the health of people worldwide, but its underlying mechanisms remain unclear. This study aims to clarify the biological function of microRNA-378b (miR-378b) in ethanol (EtOH)-induced hepatic lipid accumulation. Here, we report miR-378b is over-expressed in EtOH-induced cells and EtOH-fed mice and finally accelerates lipid accumulation. MiR-378b directly targets Ca 2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2), a kinase of AMP-activated protein kinase (AMPK), and mediates the protein level of CaMKK2. Over-expression of miR-378b exacerbated the lipid accumulation induced by EtOH and inhibited CaMKK2 and the AMPK cascade while inhibition of miR-378b ameliorated lipid metabolism dysfunction in vivo and in vitro. In brief, our results show that miR-378b plays an important role in the regulation of lipid metabolism by directly targeting CaMKK2.

MiRNAs in Alcohol-Related Liver Diseases and Hepatocellular Carcinoma: A Step toward New Therapeutic Approaches?

“…Created by Biorender.com. Hepatocyte [42] Figure 1. Spectrum of Alcohol-related Liver Disease with deregulated microRNAs at each stage and cited in this review and detailed in Table 1.…”

The role of CaMKK2 in Golgi-associated vesicle trafficking

“…One example of a CaMKK2-binding protein that was identified by mass spectrometry and has expanded our understanding of the functional repertoire of CaMKK2 is fatty acid synthase (FASN) [ 24 ]. Functional studies show that the down-regulation of CaMKK2 by microRNA and in knockout mice generates a significant increase in lipid accumulation along with increased levels of FASN and SREBP1c, indicating either a direct or indirect relationship between FASN and CaMKK2 signalling [ 27 , 28 ]. Mapping of the kinome of CaMKK2 using quantitative phospho-proteomics of cells treated with the inhibitor STO-609 also enhance our understanding of the function of the protein.…”

MicroRNA regulation of AMPK in nonalcoholic fatty liver disease

“…CaMKK2 promotes gluconeogenesis and suppresses lipogenesis in the liver in part by regulating AMPK activity 54 . MiR-378b is induced by ethanol treatment in both mouse and human hepatocyte cell lines and promotes hepatic lipid accumulation by directly targeting CaMKK2 55 . The elevation in miR-378b levels results in reduced CaMKK2 expression, thereby reducing p-AMPK and p-ACC levels and causing increased lipid accumulation in vitro and in vivo.…”

“…The elevation in miR-378b levels results in reduced CaMKK2 expression, thereby reducing p-AMPK and p-ACC levels and causing increased lipid accumulation in vitro and in vivo. Conversely, inhibition of miR-378b protects mice against ethanol-induced hepatic steatosis 55 .…”