Abstract
Sirtuins (SIRTs) are master metabolic regulators with protective roles against obesity and obesity-associated metabolic disorders, including non-alcoholic fatty liver disease (NAFLD) and type-2 diabetes. We aimed to ascertain whether there is a relationship between serum SIRT1 and liver steatosis severity in obese patients. Seventy-two obese patients (BMI ≥ 30 kg/m2), 18 males and 54 females, mean age 39.66 ± 12.34 years, with ultrasonographic evidence of NAFLD, were studied. BMI, transaminases, insulin, HOMA-index, HbA1c, body composition (DXA), plasma SIRT1 levels (ELISA) and representative measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL-cholesterol, triglycerides) and inflammation (ESR, CRP, fibrinogen) were evaluated. Thirty healthy lean patients were included as controls. SIRT1 was significantly lower in severe liver steatosis obese group compared to the mild steatosis group, both had lower SIRT1 plasma values compared to control lean patients (P = 0.0001). SIRT1 showed an inverse correlation with liver steatosis and HbA1c in univariate analysis (ρ = −0.386; P = 0.001; ρ = −0.300; P = 0.01, respectively). Multiple linear regression analysis showed that liver steatosis was the independent correlate of SIRT1 even after adjustment for potentially relevant variables (β = −0.442; P = 0.003). Serum SIRT1 might be a novel clinical/biochemical parameter associated with fat liver infiltration. Further studies in larger cohorts are warranted.
Similar content being viewed by others
References
D. Herranz, M. Serrano, SIRT1: recent lessons from mouse models. Nat. Rev. Cancer 10, 819–823 (2010)
Y. Yang, W. Duan, Y. Li, Z. Jin, J. Yan, S. Yu, D. Yi, Novel role of silent information regulator 1 in myocardial ischemia. Circulation 128, 2232–2240 (2013)
A.Z. Herskovits, L. Guarente, SIRT1 in Neurodevelopment and Brain Senescence. Neuron 81, 471–483 (2014)
D. Herranz, M. Munoz-Martin, M. Canamero, F. Mulero, B. Martinez-Pastor, O. Fernandez-Capetillo, M. Serrano, Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 1, 3–17 (2010)
L.R. Saunders, E. Verdin, Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26, 5489–5504 (2007)
F. Xu, D. Burk, Z. Gao, J. Yin, X. Zhang, J. Weng, J. Ye, Angiogenic deficiency and adipose tissue dysfunction are associated with macrophage malfunction in SIRT1−/− mice. Endocrinology 153, 1706–1716 (2012)
M.P. Gillum, M.E. Kotas, D.M. Erion, R. Kursawe, P. Chatterjee, K.T. Nead, E.S. Muise, J.J. Hsiao, D.W. Frederick, S. Yonemitsu, A.S. Banks, L. Qiang, S. Bhanot, J.M. Olefsky, D.D. Sears, S. Caprio, I. Shulman, SIRT1 regulates adipose tissue inflammation. Diabetes 60, 3235–3245 (2011)
K.W. Cho, C.N. Lumeng, SIRT1: a guardian at the gates of adipose tissue inflammation. Diabetes 60, 3100–3102 (2011)
L. Qiang, L. Wang, N. Kon, W. Zhao, S. Lee, Y. Zhang, W. Gu, S.R. Farmer, D. Accili, Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 150, 620–632 (2012)
Y.S. Song, S.K. Lee, Y.J. Jang, H.S. Park, J.H. Kim, Y.J. Lee, Y.S. Heo, Association between low SIRT1 expression in visceral and subcutaneous adipose tissues and metabolic abnormalities in women with obesity and type 2 diabetes. Diabetes Res. Clin. Pract. 101, 341–348 (2013)
S.B. Pedersen, J. Olholm, S.K. Paulsen, M.F. Bennetzen, B. Richelsen, Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. Int. J. Obes. 32, 1250–1255 (2008)
E. Hui, A. Xu, H. Bo Yang, K.S. Lam, Obesity as the common soil of non-alcoholic fatty liver disease and diabetes: role of adipokines. J. Diabetes Investig. 4, 413–425 (2013)
P.T. Pfluger, D. Herranz, S. Velasco-Miguel, M. Serrano, M.H. Tschöp, Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl. Acad. Sci. USA 105, 9793–9798 (2008)
F. Xu, Z. Gao, J. Zhang, C.A. Rivera, J. Yin, J. Weng, J. Ye, Lack of SIRT1 (mammalian sirtuin 1) activity leads to liver steatosis in the SIRT1 ± mice: a role of lipid mobilization and inflammation. Endocrinology 151, 2504–2514 (2010)
A. Purushotham, T.T. Schug, Q. Xu, S. Surapureddi, X. Guo, X. Li, Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9, 327–338 (2009)
D.R. Matthews, J.P. Hosker, Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985)
G. Iacobellis, G. Barbarini, C. Letizia, G. Barbaro, Epicardial fat thickness and nonalcoholic fatty liver disease in obese subjects. Obesity (Silver Spring) 22, 332–336 (2014)
T.L.I. Kelly, K.E. Wilson, S.B. Heymsfield, Dual energy X-Ray absorptiometry body composition reference values from NHANES. PLoS ONE 4, e7038 (2009)
J.M. Pappachan, A.A. Farrah, M. Edavalath, A. Mukherjee, Non-alcoholic fatty liver disease: a diabetologist’s perspective. Endocrine 45, 344–353 (2014)
P. Angulo, Nonalcoholic fatty liver disease. N. Engl. J. Med. 346, 1221–1231 (2002)
G. Marchesini, S. Moscatiello, S. Di Domizio, G. Forlani, Obesity-associated liver disease. J. Clin. Endocrinol. Metab. 93 (11 Suppl 1), S74–S80 (2008)
G. Targher, C.P. Day, E. Bonora, Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363, 1341–1350 (2010)
A. Kotronen, H. Yki-Jarvinen, Fatty liver: a novel component of the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 28, 27–38 (2008)
S. Sookoian, T.F. Gianotti, M.S. Rosselli, A.L. Burgueño, G.O. Castaño, C.J. Pirola, Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 218, 378–385 (2011)
S.A. Mirbagheri, A. Rashidi, S. Abdi, D. Saedi, M. Abouzari, Liver: an alarm for the heart? Liver Int. 27, 891–894 (2007)
P. Pisto, M. Santaniemi, R. Bloigu, O. Ukkola, Y.A. Kesäniemi, Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ Open 4, e004973 (2014). doi:10.1136/bmjopen-2014-004973
S. Mariani, D. Fiore, G. Barbaro, S. Basciani, M. Saponara, E. D’Arcangelo, S. Ulisse, C. Moretti, A. Fabbri, L. Gnessi, Association of epicardial fat thickness with the severity of obstructive sleep apnea in obese patients. Int. J. Cardiol. 167, 2244–2249 (2013)
M.E. Kotas, M.C. Gorecki, M.P. Gillum, Sirtuin-1 is a nutrient-dependent modulator of inflammation. Adipocyte 2, 113–118 (2013)
H. Lee, S.H. Chu, J.Y. Park, H.K. Park, J.A. Im, J.W. Lee, Visceral adiposity is associated with SIRT1 expression in peripheral blood mononuclear cells: a pilot study. Endocr. J. 60, 1269–1273 (2013)
Y. Li, L. Liu, B. Wang, J. Wang, D. Chen, Simple steatosis is a more relevant source of serum inflammatory markers than omental adipose tissue. Clin. Res. Hepatol. Gastroenterol. 38, 46–54 (2014)
F. Yeung, J.E. Hoberg, C.S. Ramsey, M.D. Keller, D.R. Jones, R.A. Frye, M.W. Mayo, Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004)
M. Kitada, D. Koya, SIRT1 in Type 2 diabetes: mechanisms and therapeutic potential. Diabetes. Metab. J. 37, 315–325 (2013)
L. Bordone, M.C. Motta, F. Picard, A. Robinson, U.S. Jhala, J. Apfeld, T. McDonagh, M. Lemieux, M. McBurney, A. Szilvasi, E.J. Easlon, S.J. Lin, L. Guarente, Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol. 4, e31 (2006)
J.H. Lee, M.Y. Song, E.K. Song, E.K. Kim, W.S. Moon, M.K. Han, J.W. Park, K.B. Kwon, B.H. Park, Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 58, 344–351 (2009)
M. Quiñones, O. Al-Massadi, J. Fernø, R. Nogueiras, Cross-talk between SIRT1 and endocrine factors: effects on energy homeostasis. Mol. Cell. Endocrinol. (2014). doi:10.1016/j.mce.2014.08.002
Y. Li, K. Wong, A. Giles, J. Jiang, J.W. Lee, A.C. Adams, A. Kharitonenkov, Q. Yang, B. Gao, L. Guarente, M. Zang, Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 146, 539–549 (2014)
A. Shannon, N. Alkhouri, C. Carter-Kent, L. Monti, R. Devito, R. Lopez, A.E. Feldstein, V. Nobili, Ultrasonographic quantitative estimation of hepatic steatosis in children with NAFLD. J. Pediatr. Gastroenterol. Nutr. 53, 190–195 (2011)
M. Noureddin, J. Lam, M.R. Peterson, M. Middleton, G. Hamilton, T.A. Le, R. Bettencourt, C. Changchien, D.A. Brenner, C. Sirlin, R. Loomba, Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 58, 1930–1940 (2013)
S. Dasarathy, J. Dasarathy, A. Khiyami, R. Joseph, R. Lopez, A.J. Mc-Cullough, Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J. Hepatol. 51, 1061–1067 (2009)
A.V. Peeters, S. Beckers, A. Verrijken, I. Mertens, P. Roevens, P.J. Peeters, W. Van Hul, F.L. Van Gaal, Association of SIRT1 gene variation with visceral obesity. Hum. Genet. 124, 431–436 (2008)
S. Imai, F.B. Johnson, R.A. Marciniak, M. McVey, P.U. Park, L. Guarente, Sir2: an NAD-dependent histone deacetylase that connects chromatin silencing, metabolism, and aging. Cold Spring Harb. Symp. Quant. Biol. 65, 297–302 (2000)
Conflict of interest
The authors have no conflict of interest to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mariani, S., Fiore, D., Basciani, S. et al. Plasma levels of SIRT1 associate with non-alcoholic fatty liver disease in obese patients. Endocrine 49, 711–716 (2015). https://doi.org/10.1007/s12020-014-0465-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-014-0465-x