Voluntary distance running prevents disease progression in mice with non-alcoholic fatty liver disease (NAFLD)

Background:

Clinical evidence strongly supports the role of life-style modifications including exercise as a primary therapy for the management of NAFLD. However, the underlying mechanisms that contribute to the beneficial effects of physical exercise related to hepatic metabolism and the hepatic immune phenotype are incompletely understood. The aim of this experimental study was to establish a reproducible mouse model of life-style intervention in non-alcoholic fatty liver disease (NAFLD) using voluntary wheel running (VWR) in order to explore the therapeutic effects of physical exercise on hepatic steatosis and inflammation sequelae.

Methods:

8 – 10-week-old, male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) for 12 weeks to induce obesity-related NAFLD or a corresponding control diet (CD). After 8 weeks of dietary feeding, mice were randomly assigned to free access to a running wheel for 4 weeks or single caged mice resembling a sedentary (SED) life-style. After the 12-week experimental period, all mice were kept sedentary and were fasted overnight before sacrifice for collection of blood and liver tissue.

Results:

VWR slowed weight gain transiently in HFD-fed mice, while CD-fed mice maintained the VWR-induced weight loss due to higher activity-related energy expenditure. Moreover, VWR did prevent HFD-induced increase of serum alanine-aminotransferase (ALT) activity, but failed to alter fasting hyperglycemia and enhanced insulin, triglyceride and total cholesterol levels in HFD-fed mice. Remarkably, although HFD-fed VWR mice developed hepatomegaly and histologically confirmed hepatic steatosis, VWR reduced hepatic fat accumulation by alterations in key liver metabolic processes including the induction of fatty acid beta-oxidation (Cpt1a, Ppargc1a) and lipogenesis inhibition (Acaca, Srebf1, Pparg) following increased activity of AMP-activated protein kinase (AMPK)-alpha, which mediates increased fatty acid utilization. Furthemore, VWR mice were completely protected from HFD-induced expression of pro-inflammatory cytokines/chemokines (Il6, Il1b, Ccl2), liver macrophage infiltration and increased hepatic nuclear factor (NF)-kappaB p65 activity.

Conclusion:

In summary, voluntary wheel running prevents further hepatic lipid accumulation by improvements in fatty acid homeostasis and suppresses the inflammatory response of intrahepatic macrophages in mice with NAFL.