Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish

Nonalcoholic fatty liver disease (NAFLD) has been associated with the function and changes in expression levels of microRNAs (miRs). MiR-7 has been proven to play an important role in many cellular processes; however, its functions in the context of liver lipogenesis remain unknown. We applied the microRNA-sponge (miR-SP) technology and generated transgenic miR-7a-SP models (hC7aSP and bC7aSP), which disrupted the activities of hepatic miR-7a and induced the early onset of NAFLD and nonalcoholic steatohepatitis (NASH) in zebrafish. We identified a novel miR-7a target, YY1, and demonstrated novel miR-7a functions to regulate zebrafish hepatic lipid metabolism by controlling YY1 stabilization through the regulation of the expression of lipogenic signaling pathways. Correspondingly, liver specific miR-7a depletion functionally promoted lipid accumulation in hC7ASP livers. NASH hC7aSP increased the expression of inflammatory genes (il-1b, il-6, tnf-alpha, ifn-gamma, nfkb2, and NF-kB) and endoplasmic reticulum stress markers (atf6, ern2, ire1, perk, hspa5 and ddit3). Molecular analysis revealed that miR-7a-SP can stabilize YY1 expression and contribute to the accumulation of hepatic triglycerides by reducing the CHOP-10 expression in the hC7aSP and then inducing the transactivation of C/EBP-alpha and PPAR-gamma expression. PPAR-gamma antagonists and miR-7a mimic treatment ameliorate hC7aSP NASH phenotypes. Conclusion: Our results suggest that miR-7a-SP acts as a lipid enhancer by directly increasing YY1 stability to disrupt CHOP 10-dependent suppression of lipogenic pathways, resulting in increased lipid accumulation. MiR-7a expression improves liver steatosis and steatohepatitis in hC7aSPs, which suggests a novel strategy for the prevention and early treatment of NASH in humans.