Indole-3-acetic acid alleviates palmitic acid-induced lipid accumulation and endoplasmic reticulum stress via sirtuin 3 in primary bovine hepatocytes

Mechanistically, 3-IAA attenuated PA-induced lipid accumulation, downregulated sterol regulatory element-binding protein 1 (SREBP-1) protein and acetyl-CoA carboxylase α (ACACA) or fatty acid synthase (FASN) mRNA, and concurrently increased peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) protein abundance and CPT1A mRNA, suggesting reduced lipogenesis and enhanced fatty acid oxidation.

In parallel, 3-IAA alleviated ER swelling and suppressed ERS at both the protein and gene levels by reducing the protein abundance of phosphorylated protein kinase R-like endoplasmic reticulum kinase (P-PERK), phosphorylated inositol-requiring enzyme 1α (P-IRE1α), and cleaved activating transcription factor 6 (ATF6) with gene expression of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and spliced X-box binding protein 1 (sXBP1).

Notably, 3-IAA increased sirtuin 3 (SIRT3) mRNA and protein expression in PA-treated hepatocytes, whereas SIRT3 knockdown partially abolished its protective effects. Collectively, these findings indicate that 3-IAA mitigates PA-induced lipid accumulation and ERS via a SIRT3-dependent pathway in bovine hepatocytes, and suggest that 3-IAA may act as an endogenous regulator of hepatic homeostasis in ketotic cows.