Hepatic Overexpression of Lysophospholipid Acyltransferase LPLAT14 / MBOAT1 Ameliorates Mild Liver Injury During Early High‐Fat Diet Feeding

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) encompasses a spectrum of conditions progressing from simple steatosis to severe steatohepatitis. During this progression, liver injury associated with lipotoxicity and altered membrane phospholipid homeostasis is thought to contribute to disease aggravation. Although lysophospholipid acyltransferases (LPLATs) regulate membrane lipid remodeling and contribute to cellular integrity, the physiological roles of several LPLATs have only partially been characterized, and the in vivo functions of LPLAT14 remain largely unknown. Here, we investigated the effects of hepatic overexpression of LPLAT14 on high‐fat diet (HFD)‐induced metabolic disorders and mild liver injury in mice using an improved adenovirus (Ad) vector. Hepatic LPLAT14 overexpression did not significantly alter body weight, systemic glucose tolerance, or hepatic lipid accumulation. Targeted lipidomics revealed that LPLAT14 overexpression selectively significantly increased oleic acid (OA)‐containing phosphatidylserine (PS) species in the liver, suggesting selective incorporation of OA into lysophosphatidylserine. This specific lipidomic remodeling significantly attenuated mild liver injury during early HFD feeding, as evidenced by reduced serum alanine aminotransferase levels at 2 weeks after Ad‐LPLAT14 treatment. However, this hepatoprotective effect was not observed in the later phase (8 weeks), when severe lipid accumulation had developed, suggesting that LPLAT14 primarily attenuates mild liver injury during early HFD feeding. Collectively, our findings suggest that LPLAT14‐mediated enrichment of OA‐containing PS attenuates mild liver injury during early HFD feeding, possibly through protection against early cellular stress.