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

Abstract

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.

Branched chain amino acids supplementation modulates TGF‐β1/Smad signaling pathway and interleukins in CCl4‐induced liver fibrosis

“…These results were in consistent with Hagiwara et al , who found that BCAAs significantly suppressed TGF‐β1 in HepG2 cells. In addition, BCAAs supplementation significantly upregulated the expression of proinflammatory cytokines (TNF‐α, IL‐6, and IL‐1β) in high‐fat diet maintained mice .…”

Middle‐ and high‐molecular weight adiponectin levels in relation to nonalcoholic fatty liver disease

“…Metabolic syndrome has a strong correlation with selective BCAA profile disturbances, whose availability affects glucose, protein, and lipid metabolism . Zhang, et al demonstrated that BCAAs triggered abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAAs directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.…”

Severe toxic acute liver injury

“…Our patient also used supplement BCAA, which increased their levels (L-leucine, L-valine, L-isoleucine). BCAA is associated with non-alcoholic fatty liver disease and injury, and it is proven that their combination with high fat diet (HFD) in experimental mice leads to increased hepatic apoptosis, and elevated circulation hepatic enzymes [18].…”

“…Symptomatic and supportive therapies were administrated with suspension of all hepatotoxic substances he had previously been using, and the patient fully recovered. The absence of prior liver disease, as well the age of the patient were certainly good prognostic factors, but the influence of hepatoprotective effect of glutamine cannot be ignored [18].…”