Astaxanthin Attenuated the Expression of Fibrogenic Genes Induced by High Glucose Alone and in Combination with Transforming Growth Factor 1β in Hepatic Stellate Cells.

Abstract

Diabetes mellitus is a major metabolic disease in the U. S. with ~10% of the U.S. adults being diabetic. Diabetes mellitus causes serious health complications. In particular, studies have shown that type II diabetes mellitus is a risk factor for non‐alcoholic steatohepatitis (NASH) and liver fibrosis. Liver fibrosis is characterized by increased accumulation of extracellular matrix (ECM) in the liver due to injury. Hepatic stellate cells (HSCs) are primarily responsible for ECM production upon their activation by liver injury and therefore they play major roles in the development of liver fibrosis. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, prevented the activation of HSCs and attenuated the expression of fibrogenic markers, such as α‐smooth muscle actin (α‐SMA) and procollagen type I α1 (COL1A1) in LX‐2 (a human HSC cell line) as well as primary mouse and human HSCs. The objective of this study was to determine if astaxanthin can ameliorate the expression of fibrogenic genes induced by glucose alone or in combination with transforming growth factor β1 (TGFβ1), a potent fibrogenic cytokine, in LX‐2 and primary human HSCs. LX‐2 cells were pretreated with either low glucose (1 g/L) or high glucose (4.5 g/L) in the absence or presence of 25 μM ASTX for 24h, followed by additional treatment with 4 ng/mL of TGFβ1. Compared with low glucose, high glucose increased mRNA of α‐SMA by ~2‐fold and the combination of high glucose and TGFβ1 further increased α‐SMA expression in LX‐2 cells. ASTX attenuated the induction of α‐SMA by glucose alone or in combination with TGFβ1 by ~60%. Consistently, we also observed the induction of α‐SMA and COL1A1 expression by high glucose alone and in combination with TGFβ1 to a more extent, which was significantly attenuated by ASTX more than 70%. We also confirmed that high glucose and high glucose/TGFβ1‐induced protein levels of α‐SMA and COL1A1 were noticeably decreased by ASTX in human primary HSCs. In conclusion, ASTX inhibits high glucose and TGFβ1‐induced fibrogenic gene expression in HSCs, suggesting that it may be used as a preventive/therapeutic agent for liver fibrosis in diabetic population.Support or Funding InformationUnited States Department of Agriculture, AFRI (2012‐67018‐19290)