Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway
Tóm tắt
Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and anti-adipogenic properties. We recently demonstrated that CA protects against steatosis in ob/ob mice. In the present report, we investigated the molecular mechanism by which CA inhibits lipids accumulation both in vivo and in vitro.
In the in vivo study, ob/ob mice were fed a standard chow diet with or without CA for 5 weeks, then their hepatocyte lipid accumulation was determined. The serum concentrations of cytokines, the levels of lipid regulatory mediators, and the hepatic metabolic and signaling molecules were also evaluated. In the in vitro study, HepG2 cells were used to further clarify the effects of CA on cellular lipid accumulation and to confirm the signaling pathways involved in these effects. CA significantly reduced hepatocyte lipid accumulation. This effect was associated with repressed levels of hepatic PPARγ, reduced expression of inflammatory cytokines such as IL-1β, IL-12, IL-17, IFN-γ, MCP-1, and MIP-1β, and increased ATP, acetyl CoA, NAD(P)+, and NAD(P)H. Other signaling molecules, such as EGFR, MAPK, AMPK, and ACC, which regulate lipid metabolism, were activated in mice fed the CA diet. CA inhibited palmitate-induced cellular lipid accumulation and stimulated the phosphorylation of both EGFR and MAPK. Pretreatment with either the EGFR inhibitor AG1478 or the MEK-specific inhibitor U0126 abolished the effects of CA on cellular lipid accumulation and decreased both the protein expression and activity of PPARγ. EGFR/MAPK signaling plays an important role in the inhibitory effect of CA on hepatocyte lipid accumulation.
Tài liệu tham khảo
Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis. 2010;9:42.
Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009;48(1):1–26.
Tessari P, Coracina A, Cosma A, Tiengo A. Hepatic lipid metabolism and non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2009;19(4):291–302.
Lelliott C, Vidal-Puig AJ. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int J Obes Relat Metab Disord. 2004;28(Suppl 4):S22–8.
Viollet B, Guigas B, Leclerc J, Hebrard S, Lantier L, Mounier R, et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf). 2009;196(1):81–98.
Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 2009;9(5):407–16.
Yang YM, Han CY, Kim YJ, Kim SG. AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability. World J Gastroenterol. 2010;16(30):3731–42.
Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem. 2003;278(36):34268–76.
Kallwitz ER, McLachlan A, Cotler SJ. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J Gastroenterol. 2008;14(1):22–8.
Burns KA, Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta. 2007;1771(8):952–60.
Bost F, Aouadi M, Caron L, Binetruy B. The role of MAPKs in adipocyte differentiation and obesity. Biochimie. 2005;87(1):51–6.
Wang T, Takikawa T, Satoh T, Yoshioka Y, Kosaka K, Tatemichi Y, et al. Carnosic acid prevents obesity and hepatic steatosis in ob/ob mice. Hepatol Res. 2011;40(6):605–12.
Aruoma OI, Halliwell B, Aeschbach R, Loligers J. Antioxidant and pro-oxidant properties of active rosemary constituents: carnosol and carnosic acid. Xenobiotica. 1992;22(2):257–68.
Satoh T, Kosaka K, Itoh K, Kobayashi A, Yamamoto M, Shimojo Y, et al. Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J Neurochem. 2008;104(4):1116–31.
Tamaki Y, Tabuchi T, Takahashi T, Kosaka K, Satoh T. Activated glutathione metabolism participates in protective effects of carnosic acid against oxidative stress in neuronal HT22 cells. Planta Med. 2009;76(7):683–8.
Takahashi T, Tabuchi T, Tamaki Y, Kosaka K, Takikawa Y, Satoh T. Carnosic acid and carnosol inhibit adipocyte differentiation in mouse 3T3–L1 cells through induction of phase2 enzymes and activation of glutathione metabolism. Biochem Biophys Res Commun. 2009;382(3):549–54.
Vock C, Gleissner M, Klapper M, Doring F. Identification of palmitate-regulated genes in HepG2 cells by applying microarray analysis. Biochim Biophys Acta. 2007;1770(9):1283–8.
Gomez-Lechon MJ, Donato MT, Martinez-Romero A, Jimenez N, Castell JV, O’Connor JE. A human hepatocellular in vitro model to investigate steatosis. Chem Biol Interact. 2007;165(2):106–16.
Kasturi R, Joshi VC. Hormonal regulation of stearoyl coenzyme A desaturase activity and lipogenesis during adipose conversion of 3T3–L1 cells. J Biol Chem. 1982;257(20):12224–30.
Gao B. Cytokines, STATs and liver disease. Cell Mol Immunol. 2005;2(2):92–100.
Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H, et al. Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology. 1999;30(4):934–43.
Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci. 2010;55(3):560–78.
Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev. 2010;11(6):430–45.
Kathirvel E, Chen P, Morgan K, French SW, Morgan TR. Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver. J Gastroenterol Hepatol. 2010;25(6):1136–43.
Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T, et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med. 2010;48(2):357–71.
Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol. 2006;87(1):1–16.
Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest. 2003;111(5):737–47.
Harrington M, Pond-Tor S, Boney CM. Role of epidermal growth factor and ErbB2 receptors in 3T3–L1 adipogenesis. Obesity. 2007;15(3):563–71.
Wang T, Wang Y, Yamashita H. Evodiamine inhibits adipogenesis via the EGFR–PKCalpha–ERK signaling pathway. FEBS Lett. 2009;583(22):3655–9.
Wang T, Wang Y, Kontani Y, Kobayashi Y, Sato Y, Mori N, et al. Evodiamine improves diet-induced obesity in a uncoupling protein-1-independent manner: involvement of antiadipogenic mechanism and extracellularly regulated kinase/mitogen-activated protein kinase signaling. Endocrinology. 2008;149(1):358–66.
Sharabani H, Izumchenko E, Wang Q, Kreinin R, Steiner M, Barvish Z, et al. Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia. Int J Cancer. 2006;118(12):3012–21.
Tsai CW, Lin CY, Lin HH, Chen JH. Carnosic acid, a rosemary phenolic compound, induces apoptosis through reactive oxygen species-mediated p38 activation in human neuroblastoma IMR-32 cells. Neurochem Res. 2011;36(12):2442–51.
Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest. 2000;105(8):1067–75.
Siegmund B, Sennello JA, Lehr HA, Batra A, Fedke I, Zeitz M, et al. Development of intestinal inflammation in double IL-10 and leptin-deficient mice. J Leukoc Biol. 2004;76(4):782–6.