Hemistepsin A inhibits T0901317-induced lipogenesis in the liver
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Hemistepsin A (HsA) is a guaianolide sesquiterpene lactone that inhibits hepatitis and liver fibrosis. We evaluated the effects of HsA on liver X receptor (LXR)-mediated hepatic lipogenesis in vitro and in vivo. Up to 10 μM, HsA did not affect the viability of HepG2 and Huh7 cells. Pretreatment with 5-10 μM HsA significantly decreased the luciferase activity of the LXR response element, which was transactivated by T0901317, GW 3965, and LXRα/retinoid X receptor α overexpression. In addition, it significantly inhibited the mRNA expression of LXRα in HepG2 and Huh7 cells. It also suppressed the expression of sterol regulatory element-binding protein-1c and lipogenic genes and reduced the triglyceride accumulation triggered by T0901317. Intraperitoneal injection of HsA (5 and 10 mg/kg) in mice significantly alleviated the T0901317-mediated increases in hepatocyte diameter and the percentage of regions in hepatic parenchyma occupied by lipid droplets. Furthermore, HsA significantly attenuated hepatic triglyceride accumulation by restoring the impaired expression of LXRα-dependent lipogenic genes caused by T0901317. Therefore, based on its inhibition of the LXRα-dependent signaling pathway, HsA has prophylactic potential for steatosis.
Abstract
Hemistepsin A (HsA) is a guaianolide sesquiterpene lactone that inhibits hepatitis and liver fibrosis. We evaluated the effects of HsA on liver X receptor (LXR)-mediated hepatic lipogenesis in vitro and in vivo. Up to 10 μM, HsA did not affect the viability of HepG2 and Huh7 cells. Pretreatment with 5-10 μM HsA significantly decreased the luciferase activity of the LXR response element, which was transactivated by T0901317, GW 3965, and LXRα/retinoid X receptor α overexpression. In addition, it significantly inhibited the mRNA expression of LXRα in HepG2 and Huh7 cells. It also suppressed the expression of sterol regulatory element-binding protein-1c and lipogenic genes and reduced the triglyceride accumulation triggered by T0901317. Intraperitoneal injection of HsA (5 and 10 mg/kg) in mice significantly alleviated the T0901317-mediated increases in hepatocyte diameter and the percentage of regions in hepatic parenchyma occupied by lipid droplets. Furthermore, HsA significantly attenuated hepatic triglyceride accumulation by restoring the impaired expression of LXRα-dependent lipogenic genes caused by T0901317. Therefore, based on its inhibition of the LXRα-dependent signaling pathway, HsA has prophylactic potential for steatosis.
참고문헌 (27)
- Ding L, "Handbook of experimental pharmacology" (2020), Springer
- Wang B, "Liver X receptors in lipid signalling and membrane homeostasis", Nat Rev Endocrinol, 14, pp.452~463 (2018)
- Hwahng SH, "Role of adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway in repression of liver X receptor-alpha-dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones", Hepatology, 49, pp.1913~1925 (2009)
- Repa JJ, "Regulation of mouse sterol regulatory element-binding protein-1c gene(SREBP-1c)by oxysterol receptors, LXRalpha and LXRbeta", Genes Dev, 14, pp.2819~2830 (2000)
- Ahn SB, "Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease", Dig Dis Sci, 59, pp.2975~2982 (2014)
- Zhang Y, "Liver LXRexpression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice", J Clin Invest, 122, pp.1688~1699 (2012)
- Pardilla-Gonzalez GF, "Sesquiterpene lactones : more than protective plant compounds with high toxicity", Crit Rev Plant Sci, 35, pp.18~37 (2016)
- Jang DS, "Hemistepsins with cytotoxic activity from Hemisteptia lyrata", Planta Med, 65, pp.765~766 (1999)
- 이종록, "지칭개에서 분리한 Hemistepsin A와 B의 비듬균에 대한 항균효과", KSBB Journal, 28(2), pp.74~79 (2013), 한국생물공학회
- Kim JK, "Hemistepsin A ameliorates acute inflammation in macrophages via inhibition of nuclear factor-B and activation of nuclear factor erythroid 2-related factor 2", Food Chem Toxicol, 111, pp.176~188 (2018)
- Kim JK, "Hemistepsin A alleviates liver fibrosis by inducing apoptosis of activated hepatic stellate cells via inhibition of nuclear factor-B and Akt", Food Chem Toxicol, 135, pp.111044~ (2020)
- Endo-Umeda K, "Differential expression and function of alternative splicing variants of human liver X receptor ", Mol Pharmacol, 81, pp.800~810 (2012)
- Mitro N, "T0901317 is a potent PXR ligand : implications for the biology ascribed to LXR", FEBS Lett, 581, pp.1721~1726 (2007)
- Schultz JR, "Role of LXRs in control of lipogenesis", Genes Dev, 14, pp.2831~2838 (2000)
- Chen G, "Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver", Proc Natl Acad Sci U S A, 101, pp.11245~11250 (2004)
- Maczewsky J, "The LXR ligand T0901317 acutely inhibits insulin secretion by affecting mitochondrial metabolism", Endocrinology, 158, pp.2145~2154 (2017)
- Dong Y, "Activation of the liver X receptor by agonist TO901317improves hepatic insulin resistance via suppressing reactive oxygen species and JNK pathway", PLoS One, 10, pp.e0124778~ (2015)
- Liang H, "Palmitic acid-induced apoptosis in pancreatic -cells is increased by liver X receptor agonist and attenuated by eicosapentaenoate", In Vivo, 25, pp.711~718 (2011)
- Choe SS, "Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis : liver X receptor-mediated lipotoxicity in pancreatic beta-cells", Diabetes, 56, pp.1534~1543 (2007)
- 권소미, "Metabolic features and regulation in cell senescence", BMB Reports, 52(1), pp.5~12 (2019), 생화학분자생물학회[DOI]
- Li Y, "AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice", Cell Metab, 13, pp.376~388 (2011)
- Fullerton MD, "AMP-activated protein kinase and its multifaceted regulation of hepatic metabolism", Curr Opin Lipidol, 27, pp.172~180 (2016)
- Shang Y, "Leucodin attenuates inflammatory response in macrophages and lipid accumulation in steatotic hepatocytes via P2x7 receptor pathway : A potential role in alcoholic liver disease", Biomed Pharmacother, 107, pp.374~381 (2018)
- Horie Y, "Hepatocytespecific Pten deficiency results in steatohepatitis and hepatocellular carcinomas", J Clin Invest, 113, pp.1774~1783 (2004)
- Sugimoto H, "Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice", Am J Physiol Gastrointest Liver Physiol, 298, pp.G283~G294 (2010)
- Jadeja RN, "Naturally occurring Nrf2 activators : potential in treatment of liver injury", Oxid Med Cell Longev, 2016, pp.3453926~ (2016)
- Choi BR, "Lemon balm and dandelion leaf extract synergistically alleviate ethanolinduced hepatotoxicity by enhancing antioxidant and antiinflammatory activity", J Food Biochem, 44, pp.e13232~ (2020)