Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.
Highlights • BCAA cause hepatic injury via complex mechanisms involving both adipocytes and hepatic cells. • In the adipocyte, BCAA activate AMPKα2 and stimulate lipolysis, increasing plasma free fatty acids (FFA), which in turn results in hepatic FFA accumulation. • In the liver, BCAA activate mTOR and inhibit FFA to TG conversion and autophagy, intensifying FFA lipotoxicity. High fat diet (HFD) induces systemic BCAA catabolic defects. Under HFD conditions, increased BCAA consumption further increases circulating BCAA abundance. BCAA-enhanced adipocyte lipolysis induces hyperlipidemia through activating AMPKα2. Elevated circulating FFA results in insulin resistance and hepatic lipotoxicity. Moreover, BCAA activate hepatic mTOR, inhibit lipogenesis and autophagy, therefore increasing hepatic susceptibility to FFA-mediated lipotoxicity. As BCAA are abundant in protein, our results call for caution regarding the ingestion of high protein diets in obesity and diabetic individuals, unless their BCAA metabolic pathways are determined normal.