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

Abstract

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 Huh 7 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.

Bromelain: a review of its mechanisms, pharmacological effects and potential applications

“…A study aiming to investigate the effects of bromelain on glucose uptake in muscle cells in vitro found that bromelain increased the glucose uptake in muscle cells by activating the protein kinase, AMPK. 99 This study further suggested that bromelain might have remarkable potential for the treatment for diabetes by improving the glucose metabolism in muscle cells. 102 Another similar study investigated the effects of bromelain on blood glucose levels in rats with diabetes, and it was found that the daily administration of bromelain for 21 days resulted in a significant reduction in blood glucose levels compared with the control group.…”

“…Research has shown that bromelain can activate AMPK in muscle cells, which in turn increases glucose uptake and its utilization by the cells. 99 This might lead to improved glucose metabolism and lower blood glucose levels, which is beneficial for individuals with diabetes. Another mechanism by which bromelain might show anti-diabetic activity is by reducing inflammation and oxidative stress.…”

Ferroptosis-Regulated Natural Products and miRNAs and Their Potential Targeting to Ferroptosis and Exosome Biogenesis

“…Auriculasin [25] Colon Ca ↓ pAIFM1 [25] Bromelain [60] Colon Ca ↑ ATG5, ATG7 [61], ACSL4 [60] Curcumin [62] Colon Ca ↑ ATF3 [63], ACSL4 [64], IREB2 [63], HMOX1 [65] ↓ SLC7A11, GPX4 [62,64], HIF1A [66], NEDD4 [67,68] Dihydroartemisinin [69] Glioma ↑ ATF4 [70,71], NCOA4 [72], HMOX1 [69] ↓ GPX4, SLC7A11, SLC3A2 [70], FTH1 [73] Dihydroisotanshinone I [74] Glioma ↑ ACSL4 [74] ↓ GPX4 [74] Diplacone [75] Lung Ca DMOCPTL [76] Breast Ca ↓ GPX4 [76] Epigallocatechin gallate [77] Pancreatic Ca ↑ ATF4 [78], ATG5, ATG7 [79], YAP1 [80] ↓ SP1, TP53 [81] Epunctanone [82] Leukemia…”

“…Auriculasin, a Flemingia philippinensis -derived flavonoid, triggers the ferroptosis and apoptosis of colon cancer cells by downregulating the ferroptosis-inhibiting protein, such as phosphorylated AIFM1 [ 25 ]. For bromelain, it suppresses hepatic lipid accumulation by upregulating ferroptosis-inducing proteins, such as phosphorylated ATG5 and ATG7, in the liver of high-fat-diet-fed mice [ 61 ]. In comparison, bromelain inhibits proliferation and induces the ferroptosis of colon cancer cells by upregulating the ferroptosis-inducing ACSL4 gene [ 60 ].…”