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As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE−/− mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

Exercise and dietary intervention are currently available strategies to treat nonalcoholic fatty liver disease (NAFLD), while the underlying mechanism remains controversial. Emerging evidence shows that lipophagy is involved in the inhibition of the lipid droplets accumulation. However, it is still unclear if exercise and dietary intervention improve NAFLD through regulating lipophagy, and how exercise of skeletal muscle can modulate lipid metabolism in liver. Moreover, NAFLD is associated with aging, and little is known about the effect of lipid accumulation on aging process. Here in vivo and in vitro models, we found that exercise and dietary intervention reduced lipid droplets formation, decreased hepatic triglyceride in the liver induced by high-fat diet. Exercise and dietary intervention enhanced the lipophagy by activating AMPK/ULK1 and inhibiting Akt/mTOR/ULK1 pathways respectively. Furthermore, exercise stimulated FGF21 production in the muscle, followed by secretion to the circulation to promote the lipophagy in the liver via an AMPK-dependent pathway. Importantly, for the first time, we demonstrated that lipid accumulation exacerbated liver aging, which was ameliorated by exercise and dietary intervention through inducing lipophagy. Our findings suggested a new mechanism of exercise and dietary intervention to improve NAFLD through promoting lipophagy. The study also provided evidence to support that muscle exercise is beneficial to other metabolic organs such as liver. The FGF21-mediated AMPK dependent lipophagy might be a potential drug target for NAFLD and aging caused by lipid metabolic dysfunction.