Endocrine Abstracts

The cholesterol oxidation product 27-hydroxycholesterol (27OHC) is enzymatically produced from cholesterol by CYP27A1 in an alternative pathway of cholesterol degradation to bile acids. This oxysterol also acts as an endogenous selective estrogen receptor modulator (SERM). In healthy humans its concentration in circulation increases in hypercholesterolemia and with age, and is associated with increased risk of atherosclerosis, cardiovascular diseases and breast cancer. Several drugs with SERM activity used for treatments of breast cancer or osteoporosis have been reported to have sporadic hepatotoxic effects. Women suffer from some liver diseases more commonly (acute liver failure, autoimmune hepatitis, benign liver lesions, or primary biliary cirrhosis). For all of these the incidence increases with advancing age. To the best of our knowledge, there is no information in the literature, clinical or experimental, relating changes in hepatic 27OHC with incidence of liver disease in the context of aging and sex. To address this problem, we examined the effect of age and sex on liver and serum concentrations of 27OHC, as well as the immunostaining pattern of CYP27A1 in the liver of four-month and 24-month-old Wistar rats (experiments were repeated twice with similar results, n=5-6 animals/group) using LC MS/MS and immunohistochemistry, respectively. Furthermore, we examined changes in total cholesterol and concentration in liver and serum, liver histopathology, as well as serum concentration of hepatic enzymes, alanine (ALT) and aspartate aminotransferase (AST). The effect of age (P<0.05) on increase of serum and hepatic 27OHC was obtained both in males and females (P<0.05) and followed the same pattern of age-related total cholesterol increase (P<0.05). However, the intrahepatic increase of 27OHC was dramatically more pronounced only in old-aged females (P<0.0001). CYP27A1 immunostaining intensity was similar in all experimental groups, being the strongest in the cytoplasm of centrilobular hepatocytes, but the immunopositivity was diffusely spread throughout the liver lobule. Histopathological analysis revealed age-related hepatocellular degeneration (swelling and hydropic degeneration, increased fraction of binuclear hepatocytes and focal fatty changes) only in females. Moreover, age-related elevation of alanine transaminase (ALT) was observed only in female rats (P<0.01). In conclusion, the obtained results confirmed age-related female-specific increase of hepatic 27OHC as well as hepatocyte degeneration obsereved only in the liver of rat females. These age-related adaptive changes in cholesterol metabolism may atenuate hepatoprotective estrogen-like effects in the liver.