Membrane-bound sn -1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res
    • Publication Information:
      Publication: 2021- : [New York] : Elsevier
      Original Publication: Memphis, Lipid Research, inc.
    • Subject Terms:
      Insulin Resistance* ; Mice, Knockout* ; Diglycerides*/metabolism ; Carrier Proteins*/metabolism ; Carrier Proteins*/genetics ; Liver*/metabolism ; Fatty Liver*/metabolism ; Fatty Liver*/genetics; Animals ; Mice ; Cell Membrane/metabolism ; Male
    • Abstract:
      Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L- Mttp -/- ) mice and age-weight matched wild-type control mice. Young (10-12-week-old) L- Mttp -/- mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L- Mttp -/- mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKCε activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L- Mttp -/- mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn -1,2-DAG content and PKCε activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L- Mttp -/- mice against the development of hepatic steatosis, increased plasma membrane sn -1,2-DAG content, PKCε activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L- Mttp -/- mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn -1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L- Mttp -/- mice as well as the development of lipid-induced hepatic insulin resistance in aged L- Mttp -/- mice.
      Competing Interests: Conflict of interest—G.I.S. is an inventor on the Yale University patent for CRMP and scientific co-founder of TLC Inc., which is developing livertargeted mitochondrial agents (including CRMP) for the treatment of NAFLD/NASH and associated metabolic diseases. There are no other conflicts of interest with the contents of this article.
      (Copyright © 2020 Abulizi et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)
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    • Grant Information:
      R01 HL137202 United States HL NHLBI NIH HHS; R01 DK113984 United States DK NIDDK NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; R01 DK121490 United States DK NIDDK NIH HHS; R01 DK116774 United States DK NIDDK NIH HHS; R01 DK119968 United States DK NIDDK NIH HHS; I01 BX004113 United States BX BLRD VA; P30 DK045735 United States DK NIDDK NIH HHS; K23 DK102874 United States DK NIDDK NIH HHS; P30 DK034989 United States DK NIDDK NIH HHS; R01 DK114793 United States DK NIDDK NIH HHS; I01 BX000901 United States BX BLRD VA
    • Contributed Indexing:
      Keywords: diabetes; drug therapy; lipids; liver; liver microsomal triglyceride transfer protein; liver-targeted mitochondrial uncoupler; metabolic disease; nonalcoholic fatty liver disease
    • Accession Number:
      0 (Diglycerides)
      0 (microsomal triglyceride transfer protein)
      0 (Carrier Proteins)
      0 (1,2-diacylglycerol)
    • Publication Date:
      Date Created: 20200910 Date Completed: 20240724 Latest Revision: 20240726
    • Publication Date:
      20240726
    • Accession Number:
      PMC7707176
    • Accession Number:
      10.1194/jlr.RA119000586
    • Accession Number:
      32907986