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The benefits of an active lifestyle are widely known: improved brain health, reduced risk of disease and stronger bones and muscles. However, some of the molecular players behind these effects remain elusive.

Regular workouts are beneficial for dyslipidemia, a metabolic condition characterized by abnormal levels of lipids in the blood. William G. Hoffman and a group of  researchers working at the Foundations of Lipids and Exercise, or , at the University of South Carolina have studied how exercise affects the angiopoietin-like protein, or ANGPTL,  complexes 3/8 and 4/8, which are considered novel targets for dyslipidemia. Their was published in the Journal of Lipid Research.

ANGPTL3, ANGPTL4 and ANGPT 8 proteins are inhibitors of lipoprotein lipase, or LPL, an enzyme primarily found on adipose and muscle tissue that acts as a pair of molecular scissors for triglycerides, breaking them down in lipoproteins, particles that transport fats and cholesterol in the blood. ANGPTL 8 forms complexes with ANGPTL3 under feeding conditions, increasing its LPL inhibitory activity, or with ANGPTL4 under fasting conditions, decreasing its LPL inhibitory activity.

“ANGPTL complexes are known to act like a sensor to regulate whether or not fats get stored for energy or used in our fat or muscles,” Hoffman said. “We want to be able to break fats down and use them when we are fasting or store them when we are fed normally. These complexes have been studied in terms of their function in fed or fasting states, but not specifically in relation to exercise.”

To study the effects of physical activity on the complexes, the researchers used records from a study of 855 adults who completed a 20-week endurance exercise training program between 1993 and 1997. They compared ANGPTL3/8 and ANGPTL4/8 levels before and after exercise training with lipolytic activities, lipids, lipoproteins and other cardiometabolic traits.

The researchers observed inverse and direct associations of ANGPTL3/8 with LPL activity, and a direct association with hepatic lipase, found primarily in the liver. They also found that ANGPTL3/8 and ANGPTL4/8 decreased with exercise training in individuals who started with the highest levels, which corresponded with improvements in lipase activity, lipid profile and cardiometabolic risk factors. These findings show ANGPTL3-4-8 as a potential novel molecular mechanism contributing to adaptations in lipid metabolism in response to exercise training

“How exercise impacts these complexes can offer valuable insight into physical activity, and how it affects our bodies at a molecular level,” Hoffman said. “The key takeaway from these studies is that regular exercise can lead to a profound improvement in fat metabolism, particularly in individuals with initially high levels of cholesterol and triglycerides.”

The exercise-induced decreases in ANGPTL3/8 levels and simultaneous improvement in lipid and lipoprotein profiles are particularly interesting from a clinical perspective. Monoclonal antibodies against this complex have decreased triglycerides in an early-stage clinical trial and in mice.

These results also reflect the potential beneficial effects of regular exercise on the ANGPTL complexes, although further research is needed to determine the extent of its impact.

“A very interesting next step is to study the relationship between the ANGPTL complexes in exercise during fed and fasting states,” Hoffman said, “and also examining the impact on the complexes of different forms of exercise, for example, cardiovascular versus strength (training).”