The role of microRNA 378 in the regulation of liver lipid metabolism
Xiaohong Wang, Hanna Vollbrecht, Heng Wu, Tianpeng Zhang, Guisheng Song.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with a prevalence estimated to be
in 20-30% of the general population within the industrialized world. It is associated with a number of risk
factors, including, type II diabetes, hepatocellular carcinoma (HCC), cardiovascular disease, and
hyperlipidemia. MicroRNAs (miRNAs) are a new class of naturally occurring small non-coding RNAs that are
known to play critical roles in a number of metabolic disorders, in part, by inhibiting expression of target genes.
It is now well established that the introduction of specific miRNAs, or antimiRs into diseased cells and tissues
can induce favorable therapeutic responses. Our miRNA profiling revealed that miR-378/378*, was significantly
induced in the livers of mice maintained on a high fat diet (HFD). Further, by inhibiting miR-378/378* we were
able to significantly prevent hepatic lipid accumulation and hyperlipidemia in HFD-treated mice. Bioinformatic
and validation studies revealed that miR-378/378* directly inhibited NRF1 (nuclear respiratory factor 1) and
SORT1 (Sortilin 1), two gatekeepers of NASH and dyslipidemia, and induced expression of TNFα, a promoter
of NASH. These findings suggest that miR-378/378* promotes hepatic lipid accumulation and the progression
of NAFLD to NASH by simultaneously modulating expression of NRF1, SORT1 and TNFα. In summary, our
findings provide novel insights into the physiological roles and mechanisms of miRNAs, in addition to their
potential therapeutic application for both of these hepatic disorders.