Red Pepper Seeds Inhibit Hepatic Lipid Accumulation by Inducing Autophagy via AMPK Activation

Abstract

Although the red pepper and its seeds have been studied for metabolic diseases, the effects and potential mechanisms of red pepper seed extract (RPS) on hepatic lipid accumulation are not yet completely understood. This study aimed to evaluate the inhibitory effect of RPS on hepatic lipid accumulation via autophagy. C57BL/6 mice were fed a high-fat diet (HFD) or a HFD supplemented with RPS. RPS treatment inhibited hepatic lipid accumulation by suppressing lipogenesis, inducing hepatic autophagic flux, and activating AMPK in HFD-fed mice. To investigate the effect of RPS on an oleic acid (OA)-induced hepatic steatosis cell model, HepG2 cells were incubated in a high-glucose medium and OA, followed by RPS treatment. RPS treatment decreased OA-induced lipid accumulation and reduced the expression of lipogenesis-associated proteins. Autophagic flux dramatically increased in the RPS-treated group. RPS phosphorylated AMPK in a dose-dependent manner, thereby dephosphorylated mTOR. Autophagy inhibition with 3-methyladenine (3-MA) antagonized RPS-induced suppression of lipogenesis-related protein expressions. Moreover, the knockdown of endogenous AMPK also antagonized the RPS-induced regulation of lipid accumulation and autophagy. Our findings provide new insights into the beneficial effects of RPS on hepatic lipid accumulation through the AMPK-dependent autophagy-mediated downregulation of lipogenesis.

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

“…It has been recently reported that natural products, including phenols, flavonoids, glycosides, quinones, terpenoids, pyrazines, alkaloids, and phenylpropanoids, have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic, and anti-aging effects, which mainly influence the AMPK/Nrf2/mTOR, Nrf2/HO-1, NAMPT/NAD(+)/SIRT, AMPK/SIRT1/PGC-1alpha and PKCs/PARPs/NF-kB signaling pathways, thereby regulating NAD(+) metabolism to prevent and treat NAFLD [ 117 ]. Hepatoprotective effects, caused by the inhibition of PI3K/Akt/mTOR signaling and effective alleviation of oxidative stress damage and ER stress induced by excessive lipid accumulation in hepatocytes, and activation of autophagy were observed for agonists of AMPK thymoquinone [ 118 ] and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) [ 119 ], agonist of GLP-1/glucagon cotadutide [ 120 ], an antagonist of sphingosine 1-phosphate receptor 2 (S1PR2) JTE-013 [ 26 ], activator of PI3K, autophagy-related genes (ATG) and agonist of Nrf2, PPARα and hemeoxygenase-1 (HO-1) pterostilbene [ 121 ], flavonoid with antioxidant properties involving CYP7A1, quercetin [ 122 ], Pueraria flavonoids [ 92 ], a novel gerotherapy compound, BIOIO-1001 [ 123 ], a natural nonenzymatic antioxidant with low toxicity schisandrin B (Sch B) [ 124 ], H1-antihistamines (AHs) [ 125 ], fat soluble polyphenol Tanshinone IIA (TsIIA) [ 126 ], purendan (PRD) [ 127 ], down-regulating the expression of p-mTOR, p-S6K1 and SREBP-1c, chrysin [ 128 ], red pepper seed extract (RPS) [ 129 ], Gardenia Fructus (GF) extracts [ 130 ], curcumin [ 131 ], and magnesium [ 132 ].…”

Unsaponifiable Matter from Wheat Bran Cultivated in Korea Inhibits Hepatic Lipogenesis by Activating AMPK Pathway

“…AMPK inhibits fatty acid synthesis by inhibiting the phosphorylation of ACC [51]. Lee et al showed that FFA treatment downregulates AMPK and ACC phosphorylation; however, the AMPK activation inhibits lipid accumulation in FFA-treated HepG2 cells [52]. AMPK regulates lipid-metabolism-related transcription factors, including SREBP1c [9].…”

Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases

“…Increased autophagic flux in HepG2 Cells and mouse hepatocytes in primary culture was also identified, and intracellular lipid content determined by bodipy staining was notably decreased by EGCG which was almost abolished after ATG5 or AMPK knockdown, indicating the crucial role of autophagy in NAFLD repression [ 100 ]. Similarly, the water extract of red peppers seed (RPS) from Capsicum annuum L. alleviated hepatic lipid accumulation through AMPK-relied and autophagy-mediated down-regulation of lipogenesis in HFD-fed mice and OA-induced steatosis cells [ 101 ]. Moreover, the major bioactive ingredient of Rehmannia (Di Huang) glutinosa DC.…”