Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation
The 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 resi...
| Autori principali: | , , , |
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| Natura: | Journal article |
| Lingua: | English |
| Pubblicazione: |
American Society for Biochemistry and Molecular Biology
2019
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| _version_ | 1826275973630263296 |
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| author | Regué, L Minichiello, L Avruch, J Dai, N |
| author_facet | Regué, L Minichiello, L Avruch, J Dai, N |
| author_sort | Regué, L |
| collection | OXFORD |
| description | The 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 (LIMP2KO) mice. Unexpectedly, the livers of LIMP2KO mice fed an HFD accumulated more triglyceride. Although hepatocyte-specific IMP2 deletion did not alter lipogenic gene expression, it substantially decreased 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 LIMP2KO mice maintained similar glucose tolerance and insulin sensitivity up to 6 months; however, by 6 months, blood glucose and serum triglycerides in the LIMP2KO 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 PPARα and CPT1A. This finding indicates that the previously observed marked protection against fatty liver conferred by global IMP2 deficiency in mice is due entirely to their reduced adiposity. |
| first_indexed | 2024-03-06T23:06:58Z |
| format | Journal article |
| id | oxford-uuid:642b1c52-e0ca-4260-bee3-9e4b0ec54c3f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:06:58Z |
| publishDate | 2019 |
| publisher | American Society for Biochemistry and Molecular Biology |
| record_format | dspace |
| spelling | oxford-uuid:642b1c52-e0ca-4260-bee3-9e4b0ec54c3f2022-03-26T18:17:20ZLiver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:642b1c52-e0ca-4260-bee3-9e4b0ec54c3fEnglishSymplectic Elements at OxfordAmerican Society for Biochemistry and Molecular Biology2019Regué, LMinichiello, LAvruch, JDai, NThe 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 (LIMP2KO) mice. Unexpectedly, the livers of LIMP2KO mice fed an HFD accumulated more triglyceride. Although hepatocyte-specific IMP2 deletion did not alter lipogenic gene expression, it substantially decreased 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 LIMP2KO mice maintained similar glucose tolerance and insulin sensitivity up to 6 months; however, by 6 months, blood glucose and serum triglycerides in the LIMP2KO 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 PPARα and CPT1A. This finding indicates that the previously observed marked protection against fatty liver conferred by global IMP2 deficiency in mice is due entirely to their reduced adiposity. |
| spellingShingle | Regué, L Minichiello, L Avruch, J Dai, N Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
| title | Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
| title_full | Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
| title_fullStr | Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
| title_full_unstemmed | Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
| title_short | Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
| title_sort | liver specific deletion of igf2 mrna binding protein 2 imp2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation |
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