Nonalcoholic fatty liver disease is associated with an altered hepatocyte microRNA profile in LDL receptor knockout mice.

MicroRNAs modulate processes associated with cell cycle control and differentiation. Here we explored the potential of microRNAs in the modulation of hepatic lipid metabolism and the development of nonalcoholic fatty liver disease. MicroRNA profiles of hepatocytes from low-density lipoprotein (LDL) receptor knockout mice fed a chow diet or a hypertriglyceridemia/fatty liver-inducing Western-type diet (WTD) were determined using quantitative real-time polymerase chain reaction. Ninety-seven of 103 microRNAs measured were expressed by hepatocytes and low variability between hepatocyte pools was observed. Feeding WTD coincided with a marked fivefold decrease in the relative expression level of miR-216 (P<.05) and miR-302a (P<.01). Interestingly, an increased hepatic miR-216 expression was detected in response to fasting. MicroRNA/biological function linkage analysis suggested that the change in hepatocyte microRNA profiles in response to high dietary lipid levels is associated with changes in cell cycle control and proliferation. In accordance with a diminished miR-302a expression on the WTD, hepatocyte mRNA expression levels of miR-302a target genes ABCA1 and in particular ELOVL6 were increased in response to WTD (twofold to ninefold). This suggests a role for miR-302a in hepatic cholesterol, fatty acid and glucose metabolism. In conclusion, we have shown that fatty liver development in LDL receptor knockout mice is associated with a significant change in the hepatocyte microRNA profile, i.e., a fivefold decrease in miR-216 and miR-302a expression. Based upon our comparative gene and microRNA expression studies it is anticipated that miR-302a may prove to be a valuable therapeutic target in the regulation of hepatic fatty acid utilization and insulin resistance.