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  • Although de novo hepatic lipogenesis contribute to liver FFA

    2018-10-23

    Although de novo hepatic lipogenesis contribute to liver FFA abundance, circulating FFA represent greater pools for hepatic FFA accumulation. Under physiologic conditions, intrahepatic FFA can be re-esterified and stored as TG in lipid droplets (Neuschwander-Tetri, 2010). Recent studies demonstrated converting FFA to TG is critical in protecting the liver from FFA-induced lipotoxicity. Clinical observations reveal patients Z-VAD-FMK manufacturer with advanced steatohepatitis express significantly reduced key hepatic lipogenic enzymes, and have increased hepatic FFA and significantly reduced hepatic TG (Nagaya et al., 2010; van der Poorten et al., 2013). Specifically, genetic interruption of hepatic TG synthesis leads to increased hepatic FFA accumulation, inflammation, fibrosis, and exacerbated liver damage (Yamaguchi et al., 2007). These results suggest that although global inhibition of hepatic de novo lipogenesis is metabolically beneficial, inhibition of hepatic FFA-TG conversion under hyperlipidemic conditions will be injurious to the liver. Our current study demonstrated that BCAA not only globally inhibited hepatic lipogenesis, but also stimulated adipocyte lipolysis, increasing circulating FFA. Unfortunately, FFA accumulated in hepatic Z-VAD-FMK manufacturer cannot be re-esterified and stored as TG, because DGAT1 (a key enzyme for TG synthesis from FFA) is inhibited by BCAA (Fig. 2C). FFA-mediated hepatic lipotoxicity is thus intensified. Our results support this conclusion: although in vivo inhibition of mTOR failed to reduce BCAA-induced hyperlipidemia, BCAA-induced liver injury was attenuated. Autophagy is a pivotal self-repair mechanism maintaining intracellular homeostasis via degradation of injured organelles and misfolded proteins in response to stress. Insufficient autophagy activates apoptosis signaling, resulting in cell death (Codogno and Meijer, 2005). In non-alcoholic fatty liver, hepatic autophagy is impaired due to mTOR activation. Restoring autophagy by rapamycin or carbamazepine treatment ameliorates disease severity (Lin et al., 2013). Furthermore, autophagy activation protects against FFA-mediated lipotoxicity both in vivo and in vitro (Lin et al., 2013; González-Rodríguez et al., 2014). In this study, we demonstrated BCAA activated mTOR and significantly inhibited hepatic autophagy in response to lipid exposure, resulting in hepatic apoptosis. Blockade of mTOR signaling by rapamycin restored hepatic autophagy response, attenuated FFA-induced lipotoxicity, and reduced hepatic apoptosis. In summary, our results demonstrated BCAA causes hepatic injury via complex mechanisms involving both adipocytes and hepatic cells. In adipocytes, BCAA activates AMPKα2 and stimulates lipolysis, increasing plasma FFA, which in turn results in hepatic FFA accumulation. In the liver, BCAA activates mTOR, which inhibits FFA to TG conversion and autophagy. Inhibition of hepatic FFA to TG conversion blocks the hepatic FFA outflow route, intensifying FFA lipotoxicity. Blockade of autophagy impedes the self-repairing mechanism protective against lipotoxicity, increasing apoptotic cell death. There exist many similarities between BCAA-induced (as demonstrated in this study) and nicotine-induced (recently reported by Zou and colleagues) metabolic alterations (Wu et al., 2015). However, BCAA-induced liver injury is far worse than that caused by nicotine. Lipolysis inhibition completely normalized the liver structure and function in nicotine-treated, but not BCAA-treated, animals due to the directly hepatocyte toxic effects of BCAA. 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. Moreover, our results call to attention that high fat is not the only harmful factor in the western meat-rich diet. The combination of high fat and high protein consumption may generate further dangerous metabolic disorders and organ injury.