Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice
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Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli.
Abstract
Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli.
참고문헌 (27)
- Arlia-Ciommo A, "Mechanisms underlying the anti-aging, anti-tumor effects of lithocholic bile acid", Int J Mol Sci, 15, pp.16522~16543 (2014)
- Chiang JY, "Bile acids: regulation of synthesis", J Lipid Res, 50, pp.1955~1966 (2009)
- Amador-Noguez D, "Gene expression profile of long-lived Ames dwarf mice, Little mice", Aging Cell, 3, pp.423~441 (2004)
- Amador-Noguez D, "Alterations in xenobiotic metabolism in the long-lived Little mice", Aging Cell, 6, pp.453~470 (2007)
- Poupon R, "Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis?", Lancet, 1, pp.834~836 (1987)
- Lazaridis KN, "Ursodeoxycholic acid 'mechanisms of action, clinical use in hepatobiliary disorders'", J Hepatol, 35, pp.134~146 (2001)
- Zollner G, "Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic, ursodeoxycholic acid in mouse liver, kidney, intestine", J Hepatol, 39, pp.480~488 (2003)
- Trauner M, "Molecular pathogenesis of cholestasis", N Engl J Med, 339, pp.1217~1227 (1998)
- Bellentani S, "Immunomodulating, anti-apoptotic action of ursodeoxycholic acid: where are we, where should we go?", Eur J Gastroenterol Hepatol, 17, pp.137~140 (2005)
- Rodrigues CM, "Ursodeoxycholic acid may inhibit deoxycholic acidinduced apoptosis by modulating mitochondrial transmembrane potential, reactive oxygen species production", Mol Med, 4, pp.165~178 (1998)
- Lukivskaya O, "Protective effect of ursodeoxycholic acid on liver mitochondrial function in rats with alloxan-induced diabetes: link with oxidative stress", Life Sci, 80, pp.2397~2402 (2007)
- Quintero P, "Bile acid supplementation improves established liver steatosis in obese mice independently of glucagon-like peptide-1 secretion", J Physiol Biochem, 70, pp.667~674 (2014)
- Nie B, "Specific bile acids inhibit hepatic fatty acid uptake in mice", Hepatology, 56, pp.1300~1310 (2012)
- Castro RE, "miR-34a", SIRT1, J Hepatol, pp.2013, 58[DOI]
- Postic C, "Contribution of de novo fatty acid synthesis to hepatic steatosis, insulin resistance:lessons from genetically engineered mice", J Clin Invest, 118, pp.829~838 (2008)
- Pathil A, "Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis, inflammation in murine models of nonalcoholic fatty liver disease", Hepatology, 55, pp.1369~1378 (2012)
- Ye R, "Adiponectin, driver or passenger on the road to insulin sensitivity?", Mol Metab, 2, pp.133~141 (2013)
- van de Meeberg PC, "Low-dose versus high-dose ursodeoxycholic acid in cystic fibrosis-related cholestatic liver disease. Results of a randomized study with 1-year follow-up", Scand J Gastroenterol, 32, pp.369~373 (1997)
- Roda E, "Improved liver tests, greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis", Dig Liver Dis, 34, pp.523~527 (2002)
- Tsuchida T, "Ursodeoxycholic acid improves insulin sensitivity, hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice", Metabolism, 61, pp.944~953 (2012)
- Lee JM, "Ursodeoxycholic acid inhibits liver X receptor alpha-mediated hepatic lipogenesis via induction of the nuclear corepressor SMILE", J Biol Chem, 289, pp.1079~1091 (2014)
- Mueller M, "Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid, lipid metabolism in morbid obesity", J Hepatol, 62, pp.1398~1404 (2015)
- Link JC, "Increased High-Density Lipoprotein Cholesterol Levels in Mice With XX Versus XY Sex Chromosomes", Arterioscler Thromb Vasc Biol, 35, pp.1778~1786 (2015)
- Voshol PJ, "Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice", Endocrinology, 144, pp.3456~3462 (2003)
- Nunes PM, "Ursodeoxycholic acid treatment of hepatic steatosis:a (13)C NMR metabolic study", NMR Biomed, 24, pp.1145~1158 (2011)
- Chung HY, "Molecular inflammation:underpinnings of aging, age-related diseases", Ageing Res Rev, 8, pp.18~30 (2009)
- Shoelson SE, "Inflammation, insulin resistance", J Clin Invest, 116, pp.1793~1801 (2006)