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Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH
Abstract
Background/aims 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. Methods Filipin staining, indicative of FC accumulation, and real-time PCR analyses were performed in 31 NAFLD patients and in seven controls. Results 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. Conclusions 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.
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“A recent study of Cabellero and co-workers (55) suggests that SREBP2 transcript levels in NAFLD and NASH are elevated 3-and 7-fold, respectively.”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [55]
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Metadata
- Authors
- Caballero, F., Fernández, A., De Lacy, A. M., Fernández-Checa, J. C., Caballería, J., & García-Ruiz, C.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- ORCID
- Caballería, Juan
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 50
- Issue
- 4
- Pages
- 789-796
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2010101404
- Cited by
- 368
- References
- 39
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 25 · 2023: 26 · 2022: 18 · 2021: 24 · 2020: 28 · 2019: 18 · 2018: 27 · 2017: 24 · 2016: 30 · 2015: 20 · 2014: 21 · 2013: 22 · 2012: 15
- FWCI
- 12.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P50-AA11999, P50AA011999)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, free cholesterol, SREBP2, steroidogenic acute regulatory protein, cholesterol homeostasis, HMG-CoA reductase, ABCG1, acyl-CoA:cholesterol acyltransferase, fatty acid synthase, SREBP-1c, mitochondrial cholesterol transport, steatosis, fibrosis
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, Steroidogenic Acute Regulatory Protein, Adult, Animals, Cholesterol, Fatty Liver, Female, Filipin, Humans, Hydroxymethylglutaryl CoA Reductases, Male, Middle Aged, Obesity, Morbid, Phosphoproteins, RNA, Messenger, DNA Primers, Mice, Knockout, ATP-Binding Cassette Transporters, Reverse Transcriptase Polymerase Chain Reaction, Diabetes Complications, Mice, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2
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