Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH
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Advanced glycation endproducts (AGEs), final reaction products of protein with sugars, are known to contribute to various disorders, including diabetes, aspects of aging, and neurodegenerative diseases. Recently, we reported elevated levels of serum AGEs in patients with nonalcoholic steatohepatitis (NASH); further, we found that AGEs induced the generation of reactive oxygen species followed by the proliferation and activation of hepatic stellate cells, a major contributor to liver fibrosis. In this study, to explore the clinical usefulness of AGEs as a biomarker for the attenuation of NASH, we investigated whether the treatment of NASH with dyslipidemia could decrease serum levels of AGEs.
This study included 43 patients with biopsy-proven NASH with dyslipidemia. Serum glyceraldehyde-derived AGE measurements and clinical laboratory tests were performed periodically during an open-label study of atorvastatin (10 mg daily) for 12 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance tests and liver density assessment by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 22 patients.
All 43 patients had dyslipidemia. The body mass indexes and serum glucose levels did not change during the treatment. After the treatment, NASH-related metabolic parameters were significantly improved. Serum glyceraldehyde-derived AGE levels were significantly decreased (10.4 ± 3.8 and 2.5 ± 1.1 IU/mL before and after treatment, respectively). The steatosis grade and nonalcoholic fatty liver disease (NAFLD) activity score were significantly improved.
The present data demonstrated that atorvastatin decreased the serum levels of AGEs in NASH patients with dyslipidemia and suggest the usefulness of AGEs as a biomarker for the attenuation of NASH.
KeywordsNASH with dyslipidemia Atorvastatin Advanced glycation endproducts Biomarker
Nonalcoholic fatty liver disease
Glyceraldehyde-derived advanced glycation endproducts
Advanced glycation endproducts
Receptor for AGEs
Reactive oxygen species
Thiobarbituric acid reactive substances
Oral glucose tolerance test
Impaired glucose tolerance
Homeostasis model-IR: NAS
Impaired glucose tolerance
Body mass index
Tumor necrosis factor-α
Free fatty acid
Procollagen type III propeptide
- 11.Inagaki Y, Yamagishi S, Okamoto T, Takeuchi M, Amano S. Pigment epithelium-derived factor prevents advanced glycation end products-induced monocyte chemoattractant protein-1 production in microvascular endothelial cells by suppressing intracellular reactive oxygen species generation. Diabetologia. 2003;46:284–7.PubMedGoogle Scholar
- 13.Miele C, Riboulet A, Maitan MA, Oriente F, Romano C, Formisano P, et al. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. J Biol Chem. 2003;278:47376–87.CrossRefPubMedGoogle Scholar
- 17.Whalan DJ. The ethics and morality of clinical trials in man. Med J Aust. 1975;1:491–4.Google Scholar
- 19.Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(Suppl 1):S5–20.Google Scholar
- 23.Japanese Society for the Study of Obesity. New criteria of obesity (in Japanese). J Jpn Soc Study Obes. 2000;6:18–28.Google Scholar
- 25.Hatzitolios A, Savopoulos C, Lazaraki G, Sidiropoulos I, Haritanti P, Lefkopoulos A, et al. Efficacy of omega-3 acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol. 2004;23:127–8.Google Scholar
- 28.Funatsu T, Goto M, Kakuta H, Suzuki M, Ida M, Nishijima S, et al. Reduction in hepatic nonesterified fatty acid concentration after long-term treatment with atorvastatin lowers hepatic triglyceride synthesis and its secretion in sucrose-fed rats. Biochim Biophys Acta. 2002;1580:161–70.PubMedGoogle Scholar
- 32.Yamagishi SI, Matsui T, Adachi H, Takeuchi M. Positive association of circulating levels of advanced glycation end products (AGEs) with pigment epithelium-derived factor (PEDF) in a general population. Pharmacol Res. 2009; doi:10.1016/j.phrs.2009.07.003.
- 33.Nakamura K, Yamagishi S, Adachi H, Matsui T, Kurita-Nakamura Y, Takeuchi M, et al. Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes. Diabetes Metab Res Rev. 2008;24:109–14.CrossRefPubMedGoogle Scholar
- 37.Ishitobi T, Hyogo H, Yamagishi S, Kimura Y, Nabeshimai Y, Tazuma S, et al. Effects of Advanced Glycation End-products and High Glucose on Hepatocytes. Jpn Pharmacol Ther. 2008;36:189–91.Google Scholar