Age-dependent sex difference of non-alcoholic fatty liver disease in TSOD and db/db mice

Abstract

According to previous clinical studies, the prevalence of non-alcoholic fatty liver disease (NAFLD) is higher in men than women only during the reproductive age. Animal models of NAFLD that reflect sex differences in humans have not been established. In this study, we examined sex differences in the hepatic lesions of Tsumura Suzuki obese diabetes (TSOD) and db/db mice, which are representative genetic models of NAFLD. Male and female TSOD and db/db mice were fed with a normal diet and tap water ad libitum. Six male and female mice of each strain were sacrificed at the ages of 3 and 9 months, respectively, and serum biochemical, pathological, and molecular analyses were performed. Serum aspartate aminotransferase (AST) levels were significantly higher in male than female mice of both strains at the age of 3 months; however, at 9 months, significant sex differences were not observed. Similarly, alanine aminotransferase (ALT) levels were significantly higher in male mice than in female TSOD mice at the age of 3 months; however, at 9 months, significant sex differences were not observed. Image analysis of histological slides revealed that the frequency of the steatotic area was significantly higher in male than female db/db mice at the age of 3 months; however, significant sex differences were not observed at 9 months. The frequency of Sirius red-positive fibrotic area was significantly higher in male than female mice in both strains at the age of 3 months; however, significant sex differences were not observed at 9 months. Serum AST and ALT levels and hepatic steatosis and fibrosis in TSOD and db/db mice showed age-dependent sex differences consistent with those observed in human NAFLD. These mice may be suitable for studying sex differences of the disease.

SIRT2 Deficiency Aggravates Diet-Induced Nonalcoholic Fatty Liver Disease through Modulating Gut Microbiota and Metabolites

“…Men are at a higher risk of developing NAFLD than women, while women who do develop the disease are more likely to progress to advanced liver fibrosis [25][26][27]. Age is also a significant factor in NAFLD progression, as menopausal women over 50 are particularly susceptible to advanced liver fibrosis [28]. Our study did not find a significant difference between male and female mice, which might be due to the limited duration of diet induction (12 weeks) and the age of the mice (less than 20 weeks).…”

“…The microorganism association and interaction are critical to maintain the homeostasis of gut microbiota which ultimately influence host digestion, immunity, and metabolism [27]. Generally, among the microbial community, several microorganisms will play critical roles in the initiation and progression of diseases and are usually called driver microorganisms [28]. In our study, the correlation among all the microbial genera were subsequently analyzed (Figure S5).…”

Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma

“…Recently, Dungubat et al. 154 examined whether sex differences were present in Tsumura Suzuki obese diabetes (TSOD) and db/db mice fed a normal diet and could be age-dependent. TSOD mice represent a polygenic model of metabolic syndrome and spontaneously develop diabetes mellitus, obesity, glucosuria, hyperglycemia, and hyperinsulinemia.…”

“…For all the parameters analyzed, no significant sex differences were observed at 9 months in both strains. 154 …”

“… Dungubat et al. 154 Akr1d1 −/− mice fed a standard diet until 10 weeks of age and then transferred to HFD for 20 weeks Partial protection against diet-induced hypertriglyceridemia but not glucose intolerance or insulin resistance in male Akr1d1 −/− mice. Gathercole et al.…”