LPCAT3/LPLAT12 deficiency in the liver ameliorates acetaminophen‐induced acute liver injury

• Published in: The FASEB journal 2024-01, Vol.38 (1), p.e23328-n/a
• Main Authors: Inagaki, Natsuko F., Nakanishi, Hiroki, Ohto, Takayo, Shindou, Hideo, Shimizu, Takao
• Format: Article
• Language: English
• Subjects: 1-Acylglycerophosphocholine O-Acyltransferase; acetaminophen; Acetaminophen - toxicity; acute liver failure; Animals; Hepatocytes; Liver Failure, Acute; lysophosphatidylcholine acyltransferase 3; lysophospholipid acyltransferase 12; Mice; Mice, Knockout; oxidized phospholipids; polyunsaturated fatty acids (PUFAs)
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202301744R

Acetaminophen (APAP) is a double‐edged sword, mainly depending on the dosage. A moderate dose of APAP is effective for fever and pain relief; however, an overdose induces acute liver injury. The mechanism underlying APAP‐induced acute liver failure is unclear, and its treatment is limited. A recent report has shown that several oxidized phospholipids are associated with APAP‐induced acute liver failure. Lysophosphatidylcholine acyltransferase 3 (Lpcat3, Lplat12), which is highly expressed in the liver, preferentially catalyzes the incorporation of arachidonate into lysophospholipids (PLs). In the present study, we investigated the roles of Lpcat3 on APAP‐induced acute liver injury using liver‐specific Lpcat3‐knockout mice. Hepatic Lpcat3 deficiency reduced the degree of APAP‐induced necrosis of hepatocytes around Zone 3 and ameliorated the elevation of hepatic injury serum marker levels, and prolonged survival. Lipidomic analysis showed that the accumulation of oxidized and hydroperoxidized phospholipids was suppressed in Lpcat3‐knockout mice. The amelioration of APAP‐induced acute liver injury was due not only to the reduction in the lipid synthesis of arachidonic acid PLs because of Lpcat3 deficiency, but also to the promotion of the APAP detoxification pathway by facilitating the conjugation of glutathione and N‐acetyl‐p‐benzoquinone imine. Our findings suggest that Lpcat3 is a potential therapeutic target for treating APAP‐induced acute liver injury. Roles of Lpcat3 on APAP‐induced acute liver injury using liver‐specific Lpcat3‐knockout mice. The amelioration of APAP‐induced acute liver injury was due not only to the reduction in the lipid synthesis of arachidonic acid PLs because of Lpcat3 deficiency, but also to the promotion of the APAP detoxification pathway by facilitating the conjugation of glutathione and N‐acetyl‐p‐benzoquinone imine.