Enhancing Hepatic MBOAT7 Expression Does Not Improve Nonalcoholic Steatohepatitis in Mice

Sharpe, M. C.; Pyles, K. D.; Hallcox, T.; Kamm, D. R.; Piechowski, M.; Fisk, B.; Albert, C. J.; Carpenter, D. H.; Ulmasov, B.; Ford, D. A.; Neuschwander-Tetri, B. A.; McCommis, K. S.

doi:10.1101/2022.03.24.485677

bioRxiv · 10.1101/2022.03.24.485677

Enhancing Hepatic MBOAT7 Expression Does Not Improve Nonalcoholic Steatohepatitis in Mice

Sharpe, M. C.·Pyles, K. D.·Hallcox, T.·Kamm, D. R.·Piechowski, M.·Fisk, B.·Albert, C. J.·Carpenter, D. H.·Ulmasov, B.·Ford, D. A.·Neuschwander-Tetri, B. A.·McCommis, K. S.

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Abstract

Background & AimsGenetic analyses of human NASH have revealed polymorphisms near the membrane bound O-acyl transferase domain containing 7 (MBOAT7) gene associated with worsened liver injury. NAFLD/NASH also appears to decrease MBOAT7 expression or activity independent of these polymorphisms. Thus, we hypothesized that enhancing MBOAT7 function in NASH would improve pathology. Approach & ResultsMale C57BL6/J mice were infected with adeno-associated virus 8 (AAV8) expressing MBOAT7 under control of the hepatocyte-specific thyroid hormone-binding globulin promoter, or control virus expressing green fluorescent protein (GFP). Mice were infected after NASH induction with either choline-deficient high-fat diet or Gubra Amylin NASH diet and compared to low-fat fed control mice. Both NASH diets increased liver weights, liver triglycerides, and plasma alanine and aspartate aminotransferase (ALT and AST) markers of liver injury, which were modestly yet significantly improved by MBOAT7 overexpression. However, NASH liver histology assessed by categorical scoring was not substantially improved by MBOAT7 overexpression. MBOAT7 regulates the formation of phosphatidylinositol (PI) predominantly by arachidonoylation of lysophosphatidylinositol (LPI). Shotgun lipidomics of NASH GFP-control livers suggested decreased MBOAT7 activity in that LPI content was elevated, and both total and arachidonoylated-PI were reduced. Surprisingly, MBOAT7 overexpression did not rescue the content of most arachidonoylated PI species but did normalize or increase the abundance of several oleate and linoleate-containing PI species. Free arachidonic acid was elevated but the MBOAT7 substrate arachidonoyl-CoA was found to be low in all NASH livers compared to low-fat fed mice, likely due to decreased expression of both long-chain acyl-CoA synthetases (ACSL) 1 and 4 in NASH livers compared to controls. ConclusionsThese results suggest MBOAT7 overexpression fails to measurably improve NASH pathology potentially due to insufficient abundance of its arachidonoyl-CoA substrate in fatty livers.

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Sharpe, M. C., Pyles, K. D., Hallcox, T., Kamm, D. R., Piechowski, M., Fisk, B., Albert, C. J., Carpenter, D. H., Ulmasov, B., Ford, D. A., Neuschwander-Tetri, B. A., McCommis, K. S.. 2022-03-24. Enhancing Hepatic MBOAT7 Expression Does Not Improve Nonalcoholic Steatohepatitis in Mice. https://doi.org/10.1101/2022.03.24.485677

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