title: Turnover rates of hepatic collagen and circulating collagen-associated proteins in humans with chronic liver disease.
abstract: Accumulation and degradation of scar tissue in fibrotic liver disease occur slowly, typically over many years. Direct measurement of fibrogenesis, the rate of scar tissue deposition, may provide valuable therapeutic and prognostic information. We describe here results from a pilot study utilizing in vivo metabolic labeling to measure the turnover rate of hepatic collagen and collagen-associated proteins in plasma for the first time in human subjects. Eight subjects with chronic liver disease were labeled with daily oral doses of 2H2O for up to 8 weeks prior to diagnostic liver biopsy and plasma collection. Tandem mass spectrometry was used to measure the abundance and fractional synthesis rate (FSR) of proteins in liver and blood. Relative protein abundance and FSR data in liver revealed marked differences among subjects. FSRs of hepatic type I and III collagen ranged from 0.2-0.6% per day (half-lives of 4 months to a year) and correlated significantly with worsening histologic fibrosis. Analysis of plasma protein turnover revealed two collagen-associated proteins, lumican and transforming growth factor beta-induced-protein (TGFBI), exhibiting FSRs that correlated significantly with FSRs of hepatic collagen. In summary, this is the first direct measurement of liver collagen turnover in vivo in humans and suggests a high rate of collagen remodeling in advanced fibrosis. In addition, the FSRs of collagen-associated proteins in plasma are measurable and may provide a novel strategy for monitoring hepatic fibrogenesis rates.
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Decaris
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Emson
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gatmaitan
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Flora
authors.initials: F
authors.lastname: Luo
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Jerome
authors.initials: J
authors.lastname: Cattin
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Corelle
authors.initials: C
authors.lastname: Nakamura
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Holmes
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Angel
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Marion G
authors.initials: MG
authors.lastname: Peters
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Turner
authors.affiliation: Department of Fibrosis, KineMed Inc., Emeryville, California, United States of America; Department of Nutritional Science and Toxicology, University of California, Berkeley, California, United States of America.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D002352:Carrier Proteins / Q000097:blood*; D016000:Cluster Analysis; D003094:Collagen / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011485:Protein Binding; D020543:Proteome; D040901:Proteomics / Q000379:methods; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D020543:Proteome; D053773:Transforming Growth Factor beta1; D003094:Collagen