n-3 PUFAs inhibit TGFβ1-induced profibrogenic gene expression by ameliorating the repression of PPARγ in hepatic stellate cells

Activated hepatic stellate cells (HSCs) are primarily responsible for the accumulation of extracellular matrix substances during the development of liver fibrosis. It has been shown that n-3 polyunsaturated fatty acids (PUFAs) can prevent liver fibrosis development. However, the underlying mechanisms of action need further investigation. The objective of this study was to determine the regulatory roles of fatty adds (FAs) on the expression of profibrogenic genes in HSCs with the elucidation of mechanisms. LX-2 cells and primary human and mouse HSCs were treated with palmitic acid, oleic acid, linoleic acid, alpha-linolenic acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) to determine their effect on profibrogenic gene expression upon the activation by transforming growth factor beta 1 (TGF beta 1). PUFAs significantly suppressed TGF beta 1-induced expression of profibrogenic genes in LX-2 and primary human HSC5 with n-3 being more potent than n-6 PUFA5. However, PUFAs did not inhibit the phosphorylation and nuclear translocation of SMA- and MAD-related protein in primary human HSC5. Furthermore, PUFA5 did not alter the prolibrogenic gene expression in primary mouse HSCs. The inhibitory effect of EPA and DHA on TGF beta 1-induced profibrogenic gene expression was diminished by peroxisome proliferator-activated receptor gamma (PPARG) knockdown, although chemical inhibition of PPARy did not elicit a similar result. The results suggest that n-3 PUFAs possess the most potent protective effects against TGF beta 1-induced profibrogenic gene expression, which is, at least in part, PPAR gamma-dependent in HSCs. (C) 2020 Elsevier Inc. All rights reserved.