Sharpe Martin C, Pyles Kelly D, Hallcox Taylor, Kamm Dakota R, Piechowski Michaela, Fisk Bryan, Albert Carolyn J, Carpenter Danielle H, Ulmasov Barbara, Ford David A, Neuschwander-Tetri Brent A, McCommis Kyle S
Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri.
Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri.
Gastro Hep Adv. 2023;2(4):558-572. doi: 10.1016/j.gastha.2023.02.004. Epub 2023 Feb 23.
Polymorphisms near the membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are associated with worsened nonalcoholic fatty liver (NASH), and nonalcoholic fatty liver disease (NAFLD)/NASH may decrease MBOAT7 expression independent of these polymorphisms. We hypothesized that enhancing MBOAT7 function would improve NASH.
Genomic and lipidomic databases were mined for MBOAT7 expression and hepatic phosphatidylinositol (PI) abundance in human NAFLD/NASH. Male C57BL6/J mice were fed either choline-deficient high-fat diet or Gubra Amylin NASH diet and subsequently infected with adeno-associated virus expressing MBOAT7 or control virus. NASH histological scoring and lipidomic analyses were performed to assess MBOAT7 activity, hepatic PI, and lysophosphatidylinositol (LPI) abundance.
Human NAFLD/NASH decreases MBOAT7 expression and hepatic abundance of arachidonate-containing PI. Murine NASH models display subtle changes in MBOAT7 expression, but significantly decreased activity. After MBOAT7 overexpression, liver weights, triglycerides, and plasma alanine and aspartate transaminase were modestly improved by MBOAT7 overexpression, but NASH histology was not improved. Despite confirmation of increased activity with MBOAT7 overexpression, content of the main arachidonoylated PI species was not rescued by MBOAT7 although the abundance of many PI species was increased. Free arachidonic acid was elevated but the MBOAT7 substrate arachidonoyl-CoA was decreased in NASH livers compared to low-fat controls, likely due to the decreased expression of long-chain acyl-CoA synthetases.
Results suggest decreased MBOAT7 activity plays a role in NASH, but MBOAT7 overexpression fails to measurably improve NASH pathology potentially due to the insufficient abundance of its arachidonoyl-CoA substrate.
膜结合O-酰基转移酶结构域7（MBOAT7）基因附近的多态性与非酒精性脂肪性肝炎（NASH）病情加重相关，且非酒精性脂肪性肝病（NAFLD）/NASH可能会降低MBOAT7表达，与这些多态性无关。我们推测增强MBOAT7功能会改善NASH。
挖掘基因组和脂质组数据库，以获取人类NAFLD/NASH中MBOAT7表达及肝脏磷脂酰肌醇（PI）丰度信息。给雄性C57BL6/J小鼠喂食胆碱缺乏的高脂饮食或古布拉胰岛淀粉样多肽NASH饮食，随后用表达MBOAT7的腺相关病毒或对照病毒进行感染。进行NASH组织学评分和脂质组分析，以评估MBOAT7活性、肝脏PI和溶血磷脂酰肌醇（LPI）丰度。
人类NAFLD/NASH会降低MBOAT7表达以及含花生四烯酸的PI的肝脏丰度。小鼠NASH模型中MBOAT7表达有细微变化，但活性显著降低。MBOAT7过表达后，肝脏重量、甘油三酯以及血浆丙氨酸和天冬氨酸转氨酶有适度改善，但NASH组织学未得到改善。尽管证实MBOAT7过表达会增加活性，但MBOAT7并未使主要花生四烯酰化PI种类的含量恢复正常，不过许多PI种类的丰度增加了。与低脂对照组相比，NASH肝脏中游离花生四烯酸升高，但MBOAT7底物花生四烯酰辅酶A降低，这可能是由于长链酰基辅酶A合成酶表达降低所致。
结果表明MBOAT7活性降低在NASH中起作用，但MBOAT7过表达未能显著改善NASH病理，可能是由于其花生四烯酰辅酶A底物丰度不足。
