Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis

Apostolopoulou M, Gordillo R, Koliaki C, Gancheva S, Jelenik T, De Filippo E, Herder C, Markgraf D, Jankowiak F, Esposito I, Schlensak M, Scherer PE, Roden M (2018) Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis. Diabetes Care 41:1235–1243 Bril F, Bril F, Barb D, Portillo-Sanchez P, Biernacki D, Lomonaco R, Suman A, Weber MH, Budd JT, Lupi ME, Cusi K (2017) Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology 65:1132–1144 Cai J, Zhang XJ, Li H (2019) Progress and challenges in the prevention and control of nonalcoholic fatty liver disease. Med Res Rev 39:328–348 Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ (2018) The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67:328–357 Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–416 Dos Anjos CA (2017) F4/80 as a major macrophage marker: the case of the peritoneum and spleen. Results Probl Cell Differ 62:161–179 Drenth JPH, Schattenberg JM (2020) The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success. Expert Opin Investig Drugs 29:1365–1375 Ellis EL, Mann DA (2012) Clinical evidence for the regression of liver fibrosis. J Hepatol 56:1171–1180 Frenette C, Kayali Z, Mena E, Mantry PS, Lucas KJ, Neff G, Rodriguez M, Thuluvath PJ, Weinberg E, Bhandari BR, Robinson J, Wedick N, Chan JL, Hagerty DT, Kowdley KV (2021) Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol 74:274–282 Gancheva S, Jelenik T, Álvarez-Hernández E, Roden M (2018) Interorgan metabolic crosstalk in human insulin resistance. Physiol Rev 98:1371–1415 Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210 Hardie DG, Carling D (1997) The AMP-activated protein kinase–fuel gauge of the mammalian cell? Eur J Biochem 246:259–273 Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19 Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336:918–922 Hou XM, Wang CY, Gerwick WH, Shao CL (2019) Marine natural products as potential anti-tubercular agents. Eur J Med Chem 165:273–292 Huang BP, Lin CH, Chen HM, Lin JT, Cheng YF, Kao SH (2015) AMPK activation inhibits expression of proinflammatory mediators through downregulation of PI3K/p38 MAPK and NF-κB signaling in murine macrophages. DNA Cell Biol 34:133–141 Huh JY, Reilly SM, Abu-Odeh M, Murphy AN, Mahata SK, Zhang J, Cho Y, Seo JB, Hung CW, Green CR, Metallo CM, Saltiel AR (2020) TANK-binding kinase 1 regulates the localization of acyl-CoA synthetase ACSL1 to control hepatic fatty acid oxidation. Cell Metab 32:1012–1027 Ikarashi N, Toda T, Okaniwa T, Ito K, Ochiai W, Sugiyama K (2011) Anti-obesity and anti-diabetic effects of acacia polyphenol in obese diabetic KKAy mice fed high-fat diet. Evid Based Complement Alternat Med 2011:952031 Jian C, Fu J, Cheng X, Shen LJ, Ji YX, Wang X, Pan S, Tian H, Tian S, Liao R, Song K, Wang HP, Zhang X, Wang Y, Huang Z, She ZG, Zhang XJ, Zhu L, Li H (2020) Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell Metab 31:892–908 Kaewin S, Changsorn K, Sungkaworn T, Hiranmartsuwan P, Yaosanit W, Rukachaisirikul V, Muanprasat C (2022) Fungus-derived 3-hydroxyterphenyllin and candidusin A ameliorate palmitic acid-induced human podocyte injury via anti-oxidative and anti-apoptotic mechanisms. Molecules 27:2109 Kannt A, Wohlfart P, Madsen AN, Veidal SS, Feigh M, Schmoll D (2021) Activation of thyroid hormone receptor-β improved disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis. Br J Pharmacol 178:2412–2423 Kobayashi A, Takemura A, Koshimizu K, Nagano H, Kawazu K (1982) Candidusin A and B: new p-terphenyls with cytotoxic effects on sea urchin embryos. Agri Biol Chem 46:585–589 Li J, Liu C, Zhou Z, Dou B, Huang J, Huang L, Zheng P, Fan S, Huang C (2021) Isotschimgine alleviates nonalcoholic steatohepatitis and fibrosis via FXR agonism in mice. Phytother Res 35:3351–3364 Liu G, Cui Z, Gao X, Liu H, Wang L, Gong J, Wang A, Zhang J, Ma Q, Huang Y, Piao G, Yuan H (2021) Corosolic acid ameliorates non-alcoholic steatohepatitis induced by high-fat diet and carbon tetrachloride by regulating TGF-β1/Smad2, NF-κB, and AMPK signaling pathways. Phytother Res 35:5214–5226 Meindl-Beinker NM, Dooley S (2008) Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis. J Gastroenterol Hepatol 23(Suppl 1):S122-127 Merrill GF, Kurth EJ, Hardie DG, Winder WW (1997) AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 273:E1107-1112 Molinski TF, Dalisay DS, Lievens SL, Saludes JP (2009) Drug development from marine natural products. Nat Rev Drug Discov 8:69–85 Mottillo EP, Desjardins EM, Crane JD, Smith BK, Green AE, Ducommun S, Henriksen TI, Rebalka IA, Razi A, Sakamoto K, Scheele C, Kemp BE, Hawke TJ, Ortega J, Granneman JG, Steinberg GR (2016) Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab 24:118–129 O’Neill LA, Hardie DG (2013) Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493:346–355 Pang T, Zhang ZS, Gu M, Qiu BY, Yu LF, Cao PR, Shao W, Su MB, Li JY, Nan FJ, Li J (2008) Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J Biol Chem 283:16051–16060 Pinzani M, Marra F (2001) Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis 21:397–416 Powell EE, Wong VW, Rinella M (2021) Non-alcoholic fatty liver disease. Lancet 397:2212–2224 Rolo AP, Teodoro JS, Palmeira CM (2012) Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med 52:59–69 Rotman Y, Sanyal AJ (2017) Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut 66:180–190 Samuel VT, Shulman GI (2018) Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 27:22–41 Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403:139–148 Scheja L, Heeren J (2016) Metabolic interplay between white, beige, brown adipocytes and the liver. J Hepatol 64:1176–1186 Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078 Sun L, Cai J, Gonzalez FJ (2021) The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 18:335–347 Taylor RS, Taylor RJ, Bayliss S, Hagström H, Nasr P, Schattenberg JM, Ishigami M, Toyoda H, Wai-Sun Wong V, Peleg N, Shlomai A, Sebastiani G, Seko Y, Bhala N, Younossi ZM, Anstee QM, McPherson S, Newsome PN (2020) Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 158:1611–1625 Tian Y, Ma J, Wang W, Zhang L, Xu J, Wang K, Li D (2016) Resveratrol supplement inhibited the NF-κB inflammation pathway through activating AMPKα-SIRT1 pathway in mice with fatty liver. Mol Cell Biochem 422:75–84 Velasco G, Geelen MJ, Guzmán M (1997) Control of hepatic fatty acid oxidation by 5′-AMP-activated protein kinase involves a malonyl-CoA-dependent and a malonyl-CoA-independent mechanism. Arch Biochem Biophys 337:169–175 Wang SM, Han JJ, Ma K, Jin T, Bao L, Pei YF, Liu HW (2014) New α-glucosidase inhibitors with p-terphenyl skeleton from the mushroom Hydnellum concrescens. Fitoterapia 98:149–155 Witczak CA, Sharoff CG, Goodyear LJ (2008) AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci 65:3737–3755 Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003) LKB1is the upstream kinase in the AMP-A activated protein kinase cascade. Curr Biol 13:2004–2008 Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ (2013) Structural basis of AMPK regulation by small molecule activators. Nat Commun 4:3017 Yokozawa T, Cho EJ, Park CH, Kim JH (2012) Protective effect of proanthocyanidin against diabetic oxidative stress. Evid Based Complement Alternat Med 2012:623879 Yurchenko EA, Menchinskaya ES, Pislyagin EA, Trinh PTH, Ivanets EV, Smetanina OF, Yurchenko AN (2018) Neuroprotective activity of some marine fungal metabolites in the 6-hydroxydopamin and paraquat-induced parkinson’s disease models. Mar Drugs 16:457 Zhao P, Sun X, Chaggan C, Liao Z, In Wong K, He F, Singh S, Loomba R, Karin M, Witztum JL, Saltiel AR (2020) An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 367:652–660