Differential expression of lumican and fatty acid binding protein-1: New insights into the histologic spectrum of nonalcoholic fatty liver disease

Michael Charlton, Kimberly Viker, Anuradha Krishnan, Schuyler Sanderson, Bart Veldt, A. J. Kaalsbeek, Michael Kendrick, Geoffrey Thompson, Florencia Que, James Swain, Michael Sarr

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79 Scopus citations

Abstract

The basis of hepatocellular injury and progressive fibrosis in a subset of patients with nonalcoholic fatty liver disease (NAFLD) is poorly understood. We sought to identify hepatic proteins that are differentially abundant across the histologic spectrum of NAFLD. Hepatic protein abundance was measured in liver samples from four groups (n = 10 each) of obese (body mass index >30 kg/m2) patients: (1) obese normal group (normal liver histology), (2) simple steatosis (SS), (3) nonalcoholic steatohepatitis (NASH)-mild (steatohepatitis with fibrosis stage 0-1), and (4) NASH-progressive (steatohepatitis with fibrosis stage 2-4). Hepatic peptides were analyzed on an API Qstar XL quadrupole time-of-flight mass spectrometer using Analyst QS software. Linear trends tests were performed and used to screen for differential abundance. Nine known proteins were expressed with differential abundance between study groups. For seven proteins differential abundance is likely to have been on the basis increased hepatic lipid content and/or inflammation. Lumican, a 40-kDa keratin sulfate proteoglycan that regulates collagen fibril assembly and activates transforming growth factor-beta and smooth muscle actin, was expressed similarly in obese normal and SS but was overexpressed in a progressive manner in NASH-mild versus SS (124%, P<0.001), NASH-progressive versus NASH-mild (156%, P<0.001) and NASH-progressive versus obese normal (178%, P<0.001). Fatty acid binding protein-1 (FABP-1), which is protective against the detergent effects of excess free fatty acids, facilitates intracellular free fatty acid transport and is an important ligand for peroxisome proliferator-activated receptor-mediated transcription, was overexpressed in SS when compared to the obese normal group (128%, P < 0.001), but was paradoxically underexpressed in NASH-mild versus SS (73%,P<0.001), NASH-progressive versus NASH-mild (81%,P<0.001), and NASH-progressive versus obese normal (59%, P<0.001). Conclusion: Histologically progressive NAFLD is associated with overexpression of lumican, an important mediator of fibrosis in nonhepatic tissues, whereas FABP-1 is paradoxically underexpressed in NASH, suggesting a new potential mechanism of lipotoxicity inNAFLD.Further studies are needed to determine the biologic basis of lumican and/or FABP-1 dysregulation in NAFLD.

Original languageEnglish (US)
Pages (from-to)1375-1384
Number of pages10
JournalHepatology
Volume49
Issue number4
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Hepatology

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    Charlton, M., Viker, K., Krishnan, A., Sanderson, S., Veldt, B., Kaalsbeek, A. J., Kendrick, M., Thompson, G., Que, F., Swain, J., & Sarr, M. (2009). Differential expression of lumican and fatty acid binding protein-1: New insights into the histologic spectrum of nonalcoholic fatty liver disease. Hepatology, 49(4), 1375-1384. https://doi.org/10.1002/hep.22927