Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs)

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Abstract

Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among those with nonalcoholic fatty liver diseases (NAFLD), and some NASH patients show HCC with or without cirrhosis. In the present review we discuss fibrogenesis and the relationship between fibrosis and HCC occurrence in NASH to clarify the role of MMPs and TIMPs in both mechanisms. Previously we proposed MMP and TIMP expression in the multi-step occurrence of HCC from the literature based on viral-derived HCC. We introduce again these expressions during hepatocarcinogenesis and compare them to those in NASH-derived HCC, although the relationship with hepatic stem/progenitor cells (HPCs) invasion remains unknown. Signal transduction of MMPs and TIMPs is also discussed because it is valuable for the prevention and treatment of NASH and NASH-derived HCC.

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Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.

J. Ludwig, T Viggiano, D McGill … (1980)

Nonalcoholic steatohepatitis is a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis. Described here are findings in 20 patients with nonalcoholic steatohepatitis of unknown cause. The biopsy specimens were characterized by the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates, and, in most instances, Mallory bodies; Evidence of fibrosis was found in most specimens, and cirrhosis was diagnosed in biopsy tissue from three patients. The disease was more common in women. Most patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis. Presence of hepatomegaly and mild abnormalities of liver function were common clinical findings. Currently, we know of no effective therapy.

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The natural history of nonalcoholic fatty liver disease: a population-based cohort study.

Joseph Adams, Paul Angulo, Raymond St. Leger … (2005)

The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1-23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003-1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7-2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3-5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2-7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low.

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A matrix metalloproteinase expressed on the surface of invasive tumour cells.

H. Sato, T Takino, Y Okada … (1994)

Gelatinase A (type-IV collagenase; M(r) 72,000) is produced by tumour stroma cells and is believed to be crucial for their invasion and metastasis, acting by degrading extracellular matrix macro-molecules such as type IV collagen. An inactive precursor of gelatinase A (pro-gelatinase A) is secreted and activated in invasive tumour tissue as a result of proteolysis which is mediated by a fraction of tumour cell membrane that is sensitive to metalloproteinase inhibitors. Here we report the cloning of the complementary DNA encoding a new matrix metalloproteinase with a potential transmembrane domain. Expression of the gene product on the cell surface induces specific activation of pro-gelatinase A in vitro and enhances cellular invasion of the reconstituted basement membrane. Tumour cells of invasive lung carcinomas, which contain activated forms of gelatinase A, were found to express the transcript and the gene product. The new metalloproteinase may thus trigger invasion by tumour cells by activating pro-gelatinase A on the tumour cell surface.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 27 June 2014

Publication date Collection: September 2014

Volume: 6

Issue: 3

Pages: 1220-1255

Affiliations

[1 ]Department of Internal Medicine, Sanno Hospital, International University of Health and Welfare, Tokyo 107-0052, Japan

[2 ]Department of Internal Medicine, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan

[3 ]Preventive Medical Center, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan

[4 ]Department of Surgery, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan; E-Mails: norotaku@ 123456gmail.com (T.N.); t-nobuhiro@ 123456iuhw.ac.jp (N.T.)

[5 ]Department of Radiology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan; E-Mail: yamanouchi@ 123456iuhw.ac.jp

[6 ]Department of Pathology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan; E-Mail: hajimek@ 123456iuhw.ac.jp

[7 ]Department of Pathology, Ofuna Chuo Hospital, Kanagawa 247-0056, Japan; E-Mail: masayuki-nakano@ 123456ofunachuohp.net

[8 ]Department of Internal Medicine, Kitasato University Medical Center, Saitama 364-8501, Japan; E-Mail: yokomori@ 123456insti.kitasato-u.ac.jp

[9 ]Department of Regenerative Medicine, Tokai University School of Medicine and Institute of Medical Sciences, Isehara 259-1193, Japan; E-Mail: yutakai@ 123456is.icc.u-tokai.ac.jp

Author notes

[* ]Author to whom correspondence should be addressed; E-Mail: iokazaki@ 123456iuhw.ac.jp ; Tel.: +81-3-3402-3151; Fax: +81-3-3404-3652.

Article

Publisher ID: cancers-06-01220

DOI: 10.3390/cancers6031220

PMC ID: 4190539

PubMed ID: 24978432

SO-VID: 5c0b19cf-43e8-44d0-a506-a3673270036d

License:

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

History

Date received : 07 March 2014

Date revision received : 24 April 2014

Date accepted : 15 May 2014

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Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs)

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Numerical Algebra, Matrix Theory, Differential-Algebraic Equations, and Control Theory

Most cited references 140

Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.

The natural history of nonalcoholic fatty liver disease: a population-based cohort study.

A matrix metalloproteinase expressed on the surface of invasive tumour cells.

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