PMID- 31209109 OWN - NLM STAT- MEDLINE DCOM- 20200316 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 294 IP - 31 DP - 2019 Aug 2 TI - Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation. PG - 11944-11951 LID - 10.1074/jbc.RA119.008778 [doi] AB - 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 Imp2 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 alpha (PPARalpha). 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 PPARalpha and CPT1A 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. CI - (c) 2019 Regue et al. FAU - Regue, Laura AU - Regue L AD - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. AD - Diabetes Unit of the Medical Services, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Medicine, Harvard Medical School, Boston, MA 02115. FAU - Minichiello, Liliana AU - Minichiello L AUID- ORCID: 0000-0002-4246-4765 AD - Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom. FAU - Avruch, Joseph AU - Avruch J AUID- ORCID: 0000-0003-4940-3495 AD - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114 avruch@molbio.mgh.harvard.edu. AD - Diabetes Unit of the Medical Services, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Medicine, Harvard Medical School, Boston, MA 02115. FAU - Dai, Ning AU - Dai N AD - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114 ning@molbio.mgh.harvard.edu. AD - Diabetes Unit of the Medical Services, Massachusetts General Hospital, Boston, MA 02114. AD - Department of Medicine, Harvard Medical School, Boston, MA 02115. LA - eng GR - P30 DK040561/DK/NIDDK NIH HHS/United States GR - R37 DK017776/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190617 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Fatty Acids) RN - 0 (IGF2BP2 protein, mouse) RN - 0 (PPAR alpha) RN - 0 (Palmitates) RN - 0 (RNA-Binding Proteins) RN - 0 (Triglycerides) RN - EC 2.3.1.21 (CPT1B protein, mouse) RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) SB - IM MH - Animals MH - Carnitine O-Palmitoyltransferase/genetics/metabolism MH - Cell Line MH - Diet, High-Fat MH - Fatty Acids/*metabolism MH - Glucose Tolerance Test MH - Hypertriglyceridemia/etiology MH - Lipid Peroxidation MH - Liver/*metabolism MH - Male MH - Mice MH - Mice, Knockout MH - PPAR alpha/genetics/metabolism MH - Palmitates/metabolism MH - RNA-Binding Proteins/*genetics/metabolism MH - Triglycerides/blood/*metabolism PMC - PMC6682725 OTO - NOTNLM OT - IGF2 mRNA binding protein 2 OT - IGF2BP2 OT - IMP2 OT - RNA binding protein OT - carnitine palmitoyltransferase 1A (CPT-1A) OT - fatty acid oxidation OT - hepatocyte OT - lipid metabolism OT - liver metabolism OT - obesity OT - peroxisome proliferator-activated receptor alpha (PPARalpha) COIS- The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health EDAT- 2019/06/19 06:00 MHDA- 2020/03/17 06:00 PMCR- 2019/06/17 CRDT- 2019/06/19 06:00 PHST- 2019/04/05 00:00 [received] PHST- 2019/06/05 00:00 [revised] PHST- 2019/06/19 06:00 [pubmed] PHST- 2020/03/17 06:00 [medline] PHST- 2019/06/19 06:00 [entrez] PHST- 2019/06/17 00:00 [pmc-release] AID - S0021-9258(20)30234-9 [pii] AID - RA119.008778 [pii] AID - 10.1074/jbc.RA119.008778 [doi] PST - ppublish SO - J Biol Chem. 2019 Aug 2;294(31):11944-11951. doi: 10.1074/jbc.RA119.008778. Epub 2019 Jun 17.