Abstract
As significant differences between sexes were found in the susceptibility to alcoholic liver disease in human and animal models, it was the aim of the present study to investigate whether female mice also are more susceptible to the development of non-alcoholic fatty liver disease (NAFLD). Male and female C57BL/6J mice were fed either water or 30% fructose solution ad libitum for 16 wks. Liver damage was evaluated by histological scoring. Portal endotoxin levels and markers of Kupffer cell activation and insulin resistance, plasminogen activator inhibitor 1 (PAI-1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK ) were measured in the liver. Adiponectin mRNA expression was determined in adipose tissue. Hepatic steatosis was almost similar between male and female mice; however, inflammation was markedly more pronounced in livers of female mice. Portal endotoxin levels, hepatic levels of myeloid differentiation primary response gene (88) (MyD88) protein and of 4-hydroxynonenal protein adducts were elevated in animals with NAFLD regardless of sex. Expression of insulin receptor substrate 1 and 2 was decreased to a similar extent in livers of male and female mice with NAFLD. The less pronounced susceptibility to liver damage in male mice was associated with a superinduction of hepatic pAMPK in these mice whereas, in livers of female mice with NAFLD, PAI-1 was markedly induced. Expression of adiponectin in visceral fat was significantly lower in female mice with NAFLD but unchanged in male mice compared with respective controls. In conclusion, our data suggest that the sex-specific differences in the susceptibility to NAFLD are associated with differences in the regulation of the adiponectin-AMPK-PAI-1 signaling cascade.
Highlights
Throughout the last decades, the prevalence of nonalcoholic fatty liver disease (NAFLD) markedly increased worldwide as the prevalence of the main risk factors has reached almost epidemic proportions [1]
We found that, in specified and opportunistic pathogen-free (SOPF) mice, the development and progression of fructoseinduced steatosis was markedly slower than in specific pathogen-free (SPF) mice; the feeding period was expanded to 16 wks in the present study
Caloric Intake and Weight Gain of Male and Female Mice In Tables 1 and 2, fructose and chow intake and body weight gain of female and male mice throughout the 16-wk feeding period are summarized. Both male and female mice exposed to the 30% fructose solution reduced their general chow intake significantly; when taking caloric intake derived through the consumption of the 30% fructose solution into account, which was similar between groups, total caloric intake of both male and female fructose-fed mice exceeded that of the respective controls by ~24 kcal/mouse/d (p < 0.05 for both sexes)
Summary
Throughout the last decades, the prevalence of nonalcoholic fatty liver disease (NAFLD) markedly increased worldwide as the prevalence of the main risk factors (for example, overweight, obesity and insulin resistance) has reached almost epidemic proportions [1]. Mation of reactive oxygen species (ROS) in the liver and an induction of tumor necrosis factor α (TNFα) [4,5,6]. It was further shown in animal models of NAFLD that TNFα can alter insulindependent signaling cascades, subsequently leading to an induction of plasminogen activator inhibitor-1 (PAI-1) and alterations of the hepatic lipid export [7]. A better understanding of the biochemical and pathological changes that cause the early stages of NAFLD (for example, steatosis)
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