van den Hoek AM, de Jong JCBC, Worms N, et al. - In obese Ldlr−/−.Leiden mice, exercise, diet change, and their combination can reverse established non-alcoholic steatohepatitis (NASH)/fibrosis. Furthermore, the lifestyle interventions had beneficial impacts on atherosclerosis, white adipose tissue (WAT) inflammation and muscle function.

• Exercise and dietary changes affected more distinct pathways for steatosis and other parameters related to adiposity or lipid metabolism, which acted complementary when the interventions were combined, resulting in an additive effect for the combination therapy on important endpoints such as NASH and atherosclerosis.

• When exercise and dietary changes were combined to treat inflammation, they shared several underlying pathways, resulting in a net similar effect.

• Exercise and dietary change significantly decreased bodyweight, fat mass, adipocyte size and improved myosteatosis and muscle function with additive effects of combination treatment.

• Dietary changes lowered WAT inflammation significantly, exercise reduced it, and combination therapy showed the little additive impact.

• Exercise and diet change almost completely reversed hepatic steatosis and inflammation, while hepatic fibrosis tended to improve with exercise and was significantly improved with diet change.

• The combination therapy had additive effects for liver steatosis and associated liver lipids, as well as atherosclerosis, but not for hepatic inflammation and fibrosis.

• Pathway analysis showed a complementary impact on metabolic pathways and lipid handling processes, thereby substantiating the added value of combined lifestyle treatment.