Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis
2
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Background/Aims: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP- 1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. Methods: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/ chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. Results: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the followup period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. Conclusions: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH.
Abstract
Background/Aims: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP- 1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. Methods: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/ chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. Results: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the followup period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. Conclusions: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH.
참고문헌 (39)
- Younossi ZM, "The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe", Hepatology, 64, pp.1577~1586 (2016)[DOI]
- Sakamoto M, "Pathological findings of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease", Pathol Int, 67, pp.1~7 (2017)[DOI]
- Cohen JC, "Human fatty liver disease: old questions and new insights", Science, 332, pp.1519~1523 (2011)[DOI]
- Okazaki I, "Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis (NASH): involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs)", Cancers (Basel), 6, pp.1220~1255 (2014)[DOI]
- Moro T, "A combination of mitochondrial oxidative stress and excess fat", calorie intake accelerates steatohepatitis by enhancing hepatic CC chemokine production in mice, 2016, pp.11, e0146592~
- Henao-Mejia J, "Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity", Nature, 482, pp.179~185 (2012)[DOI]
- Bullock RE, "Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma", J Hepatol, 41, pp.685~686 (2004)[DOI]
- Yokomori H, "Spatiotemporal expression of matrix metalloproteinase-1 in progression of nonalcoholic steatohepatitis", J Mod Hum Pathol, 1, pp.11~20 (2016)[DOI]
- Yokomori H, "Hepatic progenitor cell expansion in early-stage nonalcoholic steatohepatitis: evidence from immunohistochemistry and immunoelectron microscopy of matrix metalloproteinase-1", Med Mol Morphol (2017)[DOI]
- Okazaki I, "Introduction: MMPs, ADAMs", ADAMTSs research products to achieve big dream, 2012, pp.12, 688~706
- Iimuro Y, "Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat", Gastroenterology, 124, pp.445~458 (2003)[DOI]
- Siller-Lopez F, "Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis", Gastroenterology, 126, pp.1122~1133 (2004)[DOI]
- Endo H, "Matrix metalloproteinase-13 promotes recovery from experimental liver cirrhosis in rats", Pathobiology, 78, pp.239~252 (2011)[DOI]
- Saunders WB, "MMP-1 activation by serine proteases and MMP-10 induces human capillary tubular network collapse and regression in 3D collagen matrices", J Cell Sci, 118, pp.2325~2340 (2005)[DOI]
- Brunt EM, "Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions", Am J Gastroenterol, 94, pp.2467~2474 (1999)[DOI]
- Kleiner DE, "Design and validation of a histological scoring system for nonalcoholic fatty liver disease", Hepatology, 41, pp.1313~1321 (2005)[DOI]
- Hoofnagle JH, "Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis", Aliment Pharmacol Ther, 38, pp.134~143 (2013)[DOI]
- Kanda Y, "Investigation of the freely available easy-to-use software 'EZR' for medical statistics", Bone Marrow Transplant, 48, pp.452~458 (2013)[DOI]
- Heissig B, "Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand", Cell, 109, pp.625~637 (2002)[DOI]
- Miele L, "Serum levels of hyaluronic acid and tissue metalloproteinase inhibitor- 1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease", Transl Res, 154, pp.194~201 (2009)[DOI]
- Toyoda H, "Higher hepatic gene expression and serum levels of matrix metalloproteinase-2 are associated with steatohepatitis in nonalcoholic fatty liver diseases", Biomarkers, 18, pp.82~87 (2013)[DOI]
- Marra F, "Roles for chemokines in liver disease", Gastroenterology, 147, pp.577~594 (2014)[DOI]
- Song YS, "Granulocyte- colony stimulating factor prevents the development of hepatic steatosis in rats", Ann Hepatol, 14, pp.243~250 (2015)
- Lei Y, "G-CSF enhanced SDF-1 gradient between bone marrow and liver associated with mobilization of peripheral blood CD34+ cells in rats with acute liver failure", Dig Dis Sci, 55, pp.285~291 (2010)[DOI]
- Mendt M, "Stromal-derived factor-1 and its receptor, CXCR4, are constitutively expressed by mouse liver sinusoidal endothelial cells: implications for the regulation of hematopoietic cell migration to the liver during extramedullary hematopoiesis", Stem Cells Dev, 21, pp.2142~2151 (2012)[DOI]
- Furusato B, "CXCR4 and cancer", Pathol Int, 60, pp.497~505 (2010)[DOI]
- Hong F, "Hepatic stellate cells express functional CXCR4: role in stromal cellderived factor-1alpha-mediated stellate cell activation", Hepatology, 49, pp.2055~2067 (2009)[DOI]
- Boujedidi H, "CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients", Clin Sci (Lond), 128, pp.257~267 (2015)[DOI]
- Marra F, "Modulation of liver fibrosis by adipokines", Dig Dis, 29, pp.371~376 (2011)[DOI]
- Ikejima K, "Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat", Gastroenterology, 122, pp.1399~1410 (2002)[DOI]
- De Minicis S, "Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells", Hepatology, 48, pp.2016~2026 (2008)[DOI]
- Zhou Y, "PI-3 K", AKT and ERK signaling pathways mediate leptin-induced inhibition of PPARgamma gene expression in primary rat hepatic stellate cells, 2009, pp.325, 131~139
- Machado MV, "How adiponectin, leptin, and ghrelin orchestrate together and correlate with the severity of nonalcoholic fatty liver disease", Eur J Gastroenterol Hepatol, 24, pp.1166~1172 (2012)[DOI]
- Gonciarz M, "Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin", J Pineal Res, 54, pp.154~161 (2013)[DOI]
- Willner IR, "Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease", Am J Gastroenterol, 96, pp.2957~2961 (2001)[DOI]
- Belfort R, "A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis", N Engl J Med, 355, pp.2297~2307 (2006)[DOI]
- Nakayama H, "Long term effects of pioglitazone therapy with nonalcoholic steatohepatitis", Kanzo, 50, pp.555~564 (2009)[DOI]
- Colombo M, "Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles", Annu Rev Cell Dev Biol, 30, pp.255~289 (2014)[DOI]
- Higashiyama R, "Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice", Hepatology, 45, pp.213~222 (2007)[DOI]