title: Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice.
abstract: Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 and mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Jung
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Gayong
authors.initials: G
authors.lastname: Shim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Mi-Gyeong
authors.initials: MG
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.affiliation: The Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju 501-759, Republic of Korea.
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Internal Medicine, Hanyang University School of Medicine, Seoul 133-791, Republic of Korea.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Jun
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: lee@snu.ac.kr.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001599:Berberine / Q000633:toxicity*; D018955:CD36 Antigens / Q000378:metabolism*; D020536:Enzyme Activators / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018955:CD36 Antigens; D020536:Enzyme Activators; D001599:Berberine; D055372:AMP-Activated Protein Kinases
keywords: AICAR; AMPK; Berberine; CD36; Fatty acid uptake; Fatty liver