Bromelain activates the AMP-activated protein kinase-autophagy pathway to alleviate hepatic lipid accumulation

Po-An Hu^a, Man-Chen Hsu^a, Szu-Han Chen ^b, Chia-Hui Chen^a, Yu Ru Kou ^c, Jenq-Wen Huang ^{d, **}, Tzong-Shyuan Lee^a,*

^a Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan

^b Chien Kuo Senior High School, Taipei, Taiwan

^c Department of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan

^d Nephrology division, Department of Internal Medicine, National Taiwan University Hospital YunLin Branch, YunLin, Taiwan

Bromelain, a cysteine protease found in pineapple, is known to exert protective effects against non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanism is unclear. In this study, we aimed to investigate the molecular mechanisms underlying the beneficial effects of bromelain using in vivo and in vitro models. C57BL/6 mice were fed a high-fat diet (HFD) with or without bromelain (20 mg/kg/day) for 12 weeks. We found that treatment with bromelain alleviated hepatic lipid accumulation accompanied by the activation of AMP-activated protein kinase (AMPK) and autophagy flux, as evidenced by the elevated levels of phosphorylated AMPK, ATG5, ATG7, LC3-II, and lysosome-associated membrane protein 2 (LAMP2), and the decreased levels of p62 in the liver of HFD-fed mice. In human hepatoma Huh7 cells, bromelain prevented oleic acid (OA)-induced lipid accumulation and increased the levels of phosphorylated AMPK, ATG5, ATG7, LC3-II, and LAMP2 but decreased the levels of p62. Inhibition of AMPK and autophagy flux by specific inhibitors or small interfering RNAs suppressed bromelain-mediated protective effect on lipid accumulation. Moreover, inhibition of AMPK activity abolished the activation of autophagy flux in OA-treated hepatocytes. Collectively, these findings suggest a new molecular mechanism involving the AMPK-autophagy pathway through which bromelain confers protection against the deregulation of lipid metabolism in the liver.

Keywords: AMPK; Autophagy; Bromelain; NAFLD

https://doi.org/10.38212/2224-6614.3416