Fig. 3.

Working model of our current understanding of the mechanisms by which MBOAT7 loss of function promotes liver disease progression. Either the common rs641738 (C>T) SNP or obesity/hyperinsulinemia can reduce the levels of MBOAT7 expression and enzymatic activity. When MBOAT7 function is suppressed, there is abnormal storage of triacylglycerol (TAG) in the liver (i.e., hepatic steatosis) via 1) activation of the SCAP-SREBP-1c pathway to promote canonical de novo lipogenesis; 2) (41) activation of noncanonical pathway of lipid synthesis via upregulation of CDS2 (39), or 3) the fatty acid transporter FATP1 is overexpressed facilitating lipid deposition (38). In addition, the accumulation of MBOAT7 substrate LPIs can promote steatosis (100, 102) and proinflammatory and profibrotic signaling under conditions where MBOAT7 function is diminished (37). Collectively, when MBOAT7 function is diminished, there is an imbalance in both the substrates (LPIs, fatty acyl-CoAs, or free fatty acids) and products (38:3, 38:4, and 38:5 PI and phosphorylated versions of these PI lipids) of the MBOAT7 reaction, which likely work in concert in the liver to promote the progression of liver disease from hepatic steatosis toward inflammation and fibrosis. cPLA₂, cytosolic PLA₂; G3P, glycerol-3-phosphate; LPA, lysophosphatidic acid.