The impaired hepatic PNPLA2-PPARα/δ signaling pathway is associated with lipid accumulation and inflammation in dairy cows with fatty liver

Hepatic triacylglycerol (TAG) metabolic dysregulation, characterized by concurrent enhancement of synthesis and attenuation of degradation, is fundamental to the pathogenesis of fatty liver in dairy cows. Patatin-like phospholipase domain containing 2 (PNPLA2) catalyzes the rate-limiting hydrolysis of TAG to free fatty acids (FFA). Meanwhile, peroxisome proliferator-activated receptor α/δ (PPARα/δ) promote fatty acid oxidation and inhibit inflammatory response, and are activated by FFA released during lipolysis. Given this regulatory interplay, the study investigates the hepatic status of PNPLA2, PPARα/δ signaling and PNPLA2-associated regulatory factors. The results showed that fatty liver cows exhibited a severe inflammatory response in the liver. In addition, hepatic mRNA and protein levels of PNPLA2, phosphorylated hormone-sensitive lipase, and monoacylglycerol lipase were reduced in the fatty liver cows compared with healthy cows, while those of G0/G1 switch protein 2 (G0S2) and abhydrolase domain-containing 5, lysophosphatidic acid acyltransferase (ABHD5) were not significantly different between the two groups. Notably, the hepatic transcriptional activities of PPARα and PPARδ were significantly lower in cows with fatty liver than in healthy cows. In summary, the present data indicated that fatty liver cows exhibited hepatic inhibition of the PNPLA2-PPARα/δ signaling axis and a marked inflammatory response, which may be a key factor triggering and exacerbating fatty liver. These findings not only contribute to the mechanistic insights into bovine fatty liver development but also highlight the PNPLA2-PPARα/δ signaling axis as a potential target for therapeutic intervention.