Abstract
Hepatic steatosis is frequently observed in obese and aged individuals. Because hepatic steatosis is closely associated with metabolic syndromes, including insulin resistance, dyslipidemia, and inflammation, numerous efforts have been made to develop compounds that ameliorate it. Here, a novel peroxisome proliferator-activated receptor (PPAR) α agonist, 4-(benzo[d]thiazol-2-yl)benzene-1,3-diol (MHY553) was developed, and investigated its beneficial effects on hepatic steatosis using young and old Sprague-Dawley rats and HepG2 cells.Docking simulation and Western blotting confirmed that the activity of PPARα, but not that of the other PPAR subtypes, was increased by MHY553 treatment. When administered orally, MHY553 markedly ameliorated aging-induced hepatic steatosis without changes in body weight and serum levels of liver injury markers. Consistent with in vivo results, MHY553 inhibited triglyceride accumulation induced by a liver X receptor agonist in HepG2 cells. Regarding underlying mechanisms, MHY553 stimulated PPARα translocation into the nucleus and increased mRNA levels of its downstream genes related to fatty acid oxidation, including CPT-1A and ACOX1, without apparent change in lipogenesis signaling. Furthermore, MHY553 significantly suppresses inflammatory mRNA expression in old rats. In conclusion, MHY553 is a novel PPARα agonist that improved aged-induced hepatic steatosis, in part by increasing β-oxidation signaling and decreasing inflammation in the liver. MHY553 is a potential pharmaceutical agent for treating hepatic steatosis in aging.
Highlights
Aging is often preceded by changes in biochemical predictors, including oxidative injury, increases in lipid peroxides, and DNA oxidative damage [1]
The data indicated that the Ser280 and His440 residues of PPARα were involved in hydrogen bonding with MHY553 as hydrogen acceptors and the Tyr314 residue of PPARα was found to bind with MHY553 as a hydrogen donor (Figure 1C)
These residues functioned as important determinants of activator activity and total binding affinity. These results suggested that MHY553 was a potential PPARα agonist
Summary
Aging is often preceded by changes in biochemical predictors, including oxidative injury, increases in lipid peroxides, and DNA oxidative damage [1]. The percentage of death caused by liver diseases notably increases in humans over the age of 45 years. Non-alcoholic fatty liver disease (NAFLD) is a pathological change characterized by the accumulation of www.impactjournals.com/oncotarget triglycerides in hepatocytes [3]. In the presence of a fatty liver, the hyperinsulinemic condition fails to inhibit free fatty acid flux in adipose tissues, causing free fatty acid to be absorbed by the liver [5]. This state drives triglyceride accumulation and inflammation in the liver when the lipidstoring functions of adipose tissues are overwhelmed. NAFLD is a multi-factorial disease in which tissue to tissue communication is impaired
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