Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation.

Insulin-like growth factor 2 mRNA-binding proteins 1-3 (IGF2BP1-3, also known as IMP1-3) contribute to the regulation of RNAs in a transcriptome-specific context. Global deletion of the mRNA-binding protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2 or IMP2) in mice causes resistance to obesity and fatty liver induced by a high-fat diet (HFD), whereas liver-specific IMP2 overexpression results in steatosis. To better understand the role of IMP2 in hepatic triglyceride metabolism, here we crossed mice expressing albumin-Cre with mice bearing a floxed gene to generate hepatocyte-specific IMP2 knockout (LIMP2 KO) mice. Unexpectedly, the livers of LIMP2 KO mice fed an HFD accumulated more triglyceride. Although hepatocyte-specific IMP2 deletion did not alter lipogenic gene expression, it substantially decreased the levels of the IMP2 client mRNAs encoding carnitine palmitoyltransferase 1A (CPT1A) and peroxisome proliferator-activated receptor α (PPARα). This decrease was associated with their more rapid turnover and accompanied by significantly diminished rates of palmitate oxidation by isolated hepatocytes and liver mitochondria. HFD-fed control and LIMP2 KO mice maintained a similar glucose tolerance and insulin sensitivity up to 6 months; however, by 6 months, blood glucose and serum triglycerides in LIMP2 KO mice were modestly elevated but without evidence of liver damage. In conclusion, hepatocyte-specific IMP2 deficiency promotes modest diet-induced fatty liver by impairing fatty acid oxidation through increased degradation of the IMP2 client mRNAs α and This finding indicates that the previously observed marked protection against fatty liver conferred by global IMP2 deficiency in mice is entirely due to their reduced adiposity.