Abstract
Objectives
The objectives of this study were to determine the role of histone deacetylase 9 (HDAC9) in the development of non-alcoholic steatohepatitis (NASH); and to evaluate the therapeutic effects of astaxanthin (ASTX), a xanthophyll carotenoid, on NASH via the modulation of HDAC9 in vivo.
Methods
Eight-week-old male and female wild-type (WT) and global Hdac9 knockout (KO) mice (n = 30/sex/genotype) were fed a high-fat/high-sucrose/high-cholesterol (HFHSHC) diet for 20 weeks to induce NASH. Subsequently, subsets of WT (n = 10/sex) and KO (n = 10/sex) mice were sacrificed to examine NASH features and served as baseline controls. The rest of the mice were randomly assigned into two diet groups for another 10 weeks: One continued on the HFHSHC diet, while the other group was fed an HFHSHC containing 0.03% ASTX (w/w).
Results
After 20 weeks on the HFHSHC diet, male KO mice had lower liver weights and triglycerides than WT, but no genotypic differences were observed in the female. Male KO mice showed less liver steatosis and fibrosis with significant decreases in the hepatic expression of lipogenic genes than male WT mice, but Hdac9 deletion did not inhibit NASH development in female mice. Compared with male KO baseline controls, consumption of control diet for an additional 10 week increased hepatic expression of lipogenic and pro-inflammatory genes in male KO mice, losing the beneficial effect of Hdac9 deletion shown at week 20 on the HFHSHC diet. However, the ASTX diet abrogated the induction. There were no significant differences in hepatic lipid contents and histological features of NASH between any genotypes regardless of ASTX supplementation. Also, additional control diet feeding did not induce any changes in hepatic gene expression in female mice, compared with those on the ASTX diet.
Conclusions
Hdac9 deletion protected male, but not female, mice from diet-induced hepatic steatosis and fibrosis, which may be attributable to decreased lipogenesis in the liver. However, the protection did not exist when liver damages progressed. Hdac9 deletion or ASTX alone did not alleviate the liver damage progression, but they together inhibited the induction of lipogenic and pro-inflammatory genes in the liver of male mice, indicating that they may have synergistic effects on ameliorating NASH progression.
Funding Sources
The study was supported by National Institutes of Health.
Role of histone deacetylase 9 in the development of adipose tissue senescence
