A short-term rodent model for non-alcoholic steatohepatitis induced by a high-fat diet and carbon tetrachloride.

Several models of mice-fed high-fat diets have been used to trigger non-alcoholic steatohepatitis and some chemical substances, such as carbon tetrachloride. The present study aimed to evaluate the joint action of a high-fat diet and CCl4 in developing a short-term non-alcoholic steatohepatitis model. C57BL6/J mice were divided into two groups: standard diet-fed (SD), the high-fat diet-fed (HFD) and HFD + fructose-fed and carbon tetrachloride (HFD+CCl4). The animals fed with HFD+CCl4 presented increased lipid deposition compared with both SD and HFD mice. Plasma cholesterol was increased in animals from the HFD+CCl4 group compared with the SD and HFD groups, without significant differences between the SD and HFD groups. Plasma triglycerides showed no significant difference between the groups. The HFD+CCl4 animals had increased collagen deposition in the liver compared with both SD and HFD groups. Hydroxyproline was also increased in the HFD+CCl4 group. Liver enzymes, alanine aminotransferase and aspartate aminotransferase, were increased in the HFD+CCl4 group, compared with SD and HFD groups. Also, CCl4 was able to trigger an inflammatory process in the liver of HFD-fed animals by promoting an increase of ∼2 times in macrophage activity, ∼6 times in F4/80 gene expression, and pro-inflammatory cytokines (IL-1b and TNFa), in addition to an increase in inflammatory pathway protein phosphorylation (IKKbp). HFD e HFD+CCl4 animals increased glucose intolerance compared with SD mice, associated with reduced insulin-stimulated AKT activity in the liver. Therefore, our study has shown that short-term HFD feeding associated with fructose and CCl4 can trigger non-alcoholic steatohepatitis and cause damage to glucose metabolism.

Estradiol Protects Female ApoE KO Mice against Western-Diet-Induced Non-Alcoholic Steatohepatitis.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is higher in men than in women of reproductive age, and postmenopausal women are especially susceptible to developing the disease. AIM: we evaluated if female apolipoprotein E (ApoE) KO mice were protected against Western-diet (WD)-induced NASH. METHODS: Female ovariectomized (OVX) ApoE KO mice or sham-operated (SHAM) mice were fed either a WD or a regular chow (RC) for 7 weeks. Additionally, OVX mice fed a WD were treated with either estradiol (OVX + E2) or vehicle (OVX). RESULTS: Whole-body fat, plasma glucose, and plasma insulin were increased and associated with increased glucose intolerance in OVX mice fed a WD (OVX + WD). Plasma and hepatic triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) hepatic enzymes were also increased in the plasma of OVX + WD group, which was associated with hepatic fibrosis and inflammation. Estradiol replacement in OVX mice reduced body weight, body fat, glycemia, and plasma insulin associated with reduced glucose intolerance. Treatment also reduced hepatic triglycerides, ALT, AST, hepatic fibrosis, and inflammation in OVX mice. CONCLUSIONS: These data support the hypothesis that estradiol protects OVX ApoE KO mice from NASH and glucose intolerance.

Progesterone Has No Impact on the Beneficial Effects of Estradiol Treatment in High-Fat-Fed Ovariectomized Mice.

In recent decades, clinical and experimental studies have revealed that estradiol contributes enormously to glycemic homeostasis. However, the same consensus does not exist in women during menopause who undergo replacement with progesterone or conjugated estradiol and progesterone. Since most hormone replacement treatments in menopausal women are performed with estradiol (E2) and progesterone (P4) combined, this work aimed to investigate the effects of progesterone on energy metabolism and insulin resistance in an experimental model of menopause (ovariectomized female mice-OVX mice) fed a high-fat diet (HFD). OVX mice were treated with E2 or P4 (or both combined). OVX mice treated with E2 alone or combined with P4 displayed reduced body weight after six weeks of HFD feeding compared to OVX mice and OVX mice treated with P4 alone. These data were associated with improved glucose tolerance and insulin sensitivity in OVX mice treated with E2 (alone or combined with P4) compared to OVX and P4-treated mice. Additionally, E2 treatment (alone or combined with P4) reduced both hepatic and muscle triglyceride content compared with OVX control mice and OVX + P4 mice. There were no differences between groups regarding hepatic enzymes in plasma and inflammatory markers. Therefore, our results revealed that progesterone replacement alone does not seem to influence glucose homeostasis and ectopic lipid accumulation in OVX mice. These results will help expand knowledge about hormone replacement in postmenopausal women associated with metabolic syndrome and non-alcoholic fatty liver disease.