Non-alcoholic fatty liver disease (NAFLD) pathogenesis remains unknown. Due to the emerging role of free cholesterol (FC) in NAFLD, our aim was to examine the correlation between FC accumulation in patients with NAFLD and the expression of enzymes that regulate cholesterol homeostasis.
Filipin staining, indicative of FC accumulation, and real-time PCR analyses were performed in 31 NAFLD patients and in seven controls.
All NASH patients (n = 14) and 4 out of 17 patients with steatosis exhibited filipin staining compared to controls (0 out of 7 subjects with normal liver histology and BMI). Sterol regulatory element-binding protein-2 (SREBP-2) mRNA levels were 7- and 3-fold higher in NASH and steatosis patients, respectively, compared to controls. Since hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the key enzyme in cholesterol synthesis and transcriptionally controlled by SREBP-2 we measured its mRNA levels, being 3- to 4-fold higher in NAFLD compared to controls, without any difference between NASH and steatosis patients. Fatty acid synthase (FAS) and SREBP-1c expression were not significantly induced in NAFLD, while ATP-binding cassette sub-family G member 1 (ABCG1), a transporter involved in cholesterol egress, and acyl-CoA-cholesterol acyltransferase mRNA levels were modestly increased (1.5- to 2.5-fold, p < 0.05), regardless of fibrosis. Interestingly, mRNA levels of steroidogenic acute regulatory protein (StAR), a mitochondrial-cholesterol transporting polypeptide, increased 7- and 15-fold in steatosis and NASH patients, respectively, compared to controls.
FC increases in NASH and correlates with SREBP-2 induction. Moreover, StAR overexpression in NASH suggests that mitochondrial FC may be a player in disease progression and a novel target for intervention.
Abbreviations:NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), FFA (free fatty acids), TG (triglycerides), SREBP-2 (sterol regulatory element-binding protein-2), SREBP-1c (sterol regulatory element-binding protein-1c), HMG-CoA reductase (hydroxymethylglutaryl-CoA reductase), FC (free cholesterol), ACAT (acyl-CoA-cholesterol acyltransferase), FAS (fatty acid synthase), StAR (steroidogenic acute regulatory protein), TNFα (tumor necrosis factor α), IL-6 (interleukin 6)
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Published online: January 14, 2009
Accepted: November 10, 2008
Received in revised form: November 6, 2008
Received: August 1, 2008Associate Editor: C.P. Day
☆The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this article.
© 2008 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.