Responsiveness of PNPLA3 and lipid-related transcription factors is dependent upon fatty acid profile in primary bovine hepatocytes

Abstract

AbstractKnockdown of patatin-like phospholipase domain-containing protein 3 (PNPLA3) increased triglycerides (TG) in primary bovine hepatocytes, suggesting that PNPLA3 plays a causal role in hepatic TG clearing. In vivo, PNPLA3 abundance across the periparturient period is inversely related to hepatic TG accumulation and circulating fatty acid (FA) concentrations. The purpose of this research was to determine if PNPLA3, as well as other lipases, transcription factors, or FA-mediated genes, are regulated by FA mimicking liver lipid accumulation (ACCUM) and liver lipid clearing (RECOV) or singular FA physiologically found in dairy cows at 0.5 mM of circulating RECOV (iRECOV). Abundance of PNPLA3 tended to decrease with ACCUM and increased quadratically with RECOV (P ≤ 0.10), differing from PNPLA3 expression, but consistent with previous in vivo research. Adipose TG lipase abundance, but not other lipase abundances, was quadratically responsive to both ACCUM and RECOV (P ≤ 0.005). Abundance of PNPLA3 and SREBP1c and expression of LXRA responded similarly to iRECOV, with C18:0 tending to decrease abundance (P ≤ 0.07). Results indicate that bovine PNPLA3 is translationally regulated by FA and although a LXRA-SREBP1c pathway mediation is possible, the mechanism warrants further investigation.