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Cited by 117Liver Disease Diagnosis and TreatmentLipoproteins and Cardiovascular HealthCancer, Lipids, and Metabolism

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Dissecting the multifaceted impact of statin use on fatty liver disease: a multidimensional study

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Ayada, Ibrahim, van Kleef, Laurens A., Zhang, Huai, Liu, Kuan, Li, Pengfei, Abozaid, Yasir J., Lavrijsen, Marla, Janssen, Harry L.A., van der Laan, Luc J.W., Ghanbari, Mohsen, Peppelenbosch, Maikel P., Zheng, Ming-Hua, de Knegt, Robert J., Pan, Qiuwei·2023·EBioMedicine
DOI 10.1016/j.ebiom.2022.104392PMC PMC9758527
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Abstract

BACKGROUND: Statin use could benefit patients with non-alcoholic fatty liver disease (NAFLD), but the evidence is segmented and inconclusive. This multidimensional study comprehensively investigated the potential benefits and mechanism-of-action of statins in NAFLD. METHODS: A cross-sectional investigation was performed within the Rotterdam Study (general population; n = 4.576) and the PERSONS cohort (biopsy-proven NAFLD patients; n = 569). Exclusion criteria were secondary causes for steatosis and insufficient data on alcohol, dyslipidemia or statin use. Associations of statin use with NAFLD (among entire general population), fibrosis and NASH (among NAFLD individuals and patients) were quantified. These results were pooled with available literature in meta-analysis. Last, we assessed statins' anti-lipid and anti-inflammatory effects in 3D cultured human liver organoids and THP-1 macrophages, respectively. FINDINGS: Statin use was inversely associated with NAFLD in the Rotterdam study compared to participants with untreated dyslipidemia. In the PERSONS cohort, statin use was inversely associated with NASH, but not with fibrosis. The meta-analysis included 7 studies and indicated a not significant inverse association for statin use with NAFLD (pooled-Odds Ratio: 0.69, 95% Confidence Interval: 0.46-1.01) and significant inverse associations with NASH (pooled-OR: 0.59, 95% CI: 0.44-0.79) and fibrosis (pooled-OR: 0.48, 95% CI: 0.33-0.70). In vitro, statins significantly reduced lipid droplet accumulation in human liver organoids and downregulated expression of pro-inflammatory cytokines in macrophages. INTERPRETATION: Pooled results demonstrated that statin use was associated with a lower prevalence of NASH and fibrosis and might prevent NAFLD. This may be partially attributed to the anti-lipid and anti-inflammatory characteristics of statins. Given their under-prescription, adequate prescription of statins may limit the disease burden of NAFLD. FUNDING: ZonMw, KWF, NWO, SLO, DGXII, RIDE, National and regional government, Erasmus MC and Erasmus University.

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Crossref · 10.1016/j.ebiom.2022.104392

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Fig. 1 Selection of studies. PRISMA flowchart of literature search and study identification.
Fig. 1 Selection of studies. PRISMA flowchart of literature search and study identification.CC BY · PubMed Central
Fig. 2 Forest plots showing the associations between statin use and the NAFLD disease spectrum. Random effects models were used to assess pooled odds ratio of the association between statin use and NAFLD (A), statin use and NASH (B), and statin use and fibrosis(C).
Fig. 2 Forest plots showing the associations between statin use and the NAFLD disease spectrum. Random effects models were used to assess pooled odds ratio of the association between statin use and NAFLD (A), statin use and NASH (B), and statin use and fibrosis(C).CC BY · PubMed Central
Fig. 3 Effects of simvastatin and lovastatin on lipid accumulation in 3D cultured human liver organoids. (A) Bright field images representing morphology of organoids treated with LPO only (CTR) or with LPO and different concentrations of simvastatin (20× magnification). (B) Confocal images of lipid droplets (yellow, stained by AdipoRed) and nuclei (blue, stained by Hoechst) (2000× magnification at room temperature). (C) Effect of simvastatin on the size of the induced lipid droplets; 2565, 3301, 2902, 866 lipids were captured for CTR, 0.3 μM, 3 μM and 10 μM respectively. (D) Effect of simvastatin on the number of induced lipid droplets, normalized for the amount of cells (n = 4). (E) Bright field images representing morphology of organoids treated with LPO only (CTR) or with LPO and different concentrations of lovastatin (20× magnification). (F) Confocal images of lipid droplets (yellow, stained by AdipoRed) and nuclei (blue, stained by Hoechst) (2000× magnification at room temperature). (G) Effect of lovastatin on the size of induced lipid droplets; 1772, 1686, 2390, 1728 lipids were captured for CTR, 0.3 μM, 3 μM and 10 μM respectively. (H) Effect of lovastatin on the number of induced lipid droplets, normalized for the amount of cells (n = 4). Data are presented as mean ± SD, ∗P < 0.05.
Fig. 3 Effects of simvastatin and lovastatin on lipid accumulation in 3D cultured human liver organoids. (A) Bright field images representing morphology of organoids treated with LPO only (CTR) or with LPO and different concentrations of simvastatin (20× magnification). (B) Confocal images of lipid droplets (yellow, stained by AdipoRed) and nuclei (blue, stained by Hoechst) (2000× magnification at room temperature). (C) Effect of simvastatin on the size of the induced lipid droplets; 2565, 3301, 2902, 866 lipids were captured for CTR, 0.3 μM, 3 μM and 10 μM respectively. (D) Effect of simvastatin on the number of induced lipid droplets, normalized for the amount of cells (n = 4). (E) Bright field images representing morphology of organoids treated with LPO only (CTR) or with LPO and different concentrations of lovastatin (20× magnification). (F) Confocal images of lipid droplets (yellow, stained by AdipoRed) and nuclei (blue, stained by Hoechst) (2000× magnification at room temperature). (G) Effect of lovastatin on the size of induced lipid droplets; 1772, 1686, 2390, 1728 lipids were captured for CTR, 0.3 μM, 3 μM and 10 μM respectively. (H) Effect of lovastatin on the number of induced lipid droplets, normalized for the amount of cells (n = 4). Data are presented as mean ± SD, ∗P < 0.05.CC BY · PubMed Central
Fig. 4 The effect of statin treatment on inflammatory gene expression in human macrophages. Human THP-1 monocytes were differentiated into macrophages and treated with statins. Relative gene expression is represented as CTR (untreated) and as treated with simvastatin 0.1 μM (left panel, n = 8) and lovastatin 0.1 μM (right panel, n = 6). Data are presented as mean ± SD, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001.
Fig. 4 The effect of statin treatment on inflammatory gene expression in human macrophages. Human THP-1 monocytes were differentiated into macrophages and treated with statins. Relative gene expression is represented as CTR (untreated) and as treated with simvastatin 0.1 μM (left panel, n = 8) and lovastatin 0.1 μM (right panel, n = 6). Data are presented as mean ± SD, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001.CC BY · PubMed Central

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Authors
Ayada, I., van Kleef, L. A., Zhang, H., Liu, K., Li, P., Abozaid, Y. J., Lavrijsen, M., Janssen, H. L. A., van der Laan, L. J. W., Ghanbari, M., Peppelenbosch, M. P., Zheng, M.-H., de Knegt, R. J., & Pan, Q.
Affiliations
  • Erasmus MC (NL)
  • First Affiliated Hospital of Wenzhou Medical University (CN)
  • University of Toronto (CA)
  • Wenzhou Medical University (CN)
Corresponding author
  • Zheng, Ming-Hua
  • Pan, Qiuwei
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2023-01
Volume
87
Pages
104392
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2022.104392
PMC
PMC9758527
OpenAlex
W4310847620
Cited by
117
References
48
Citations by year
2026: 26 · 2025: 40 · 2024: 43 · 2023: 8
FWCI
3.62
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministerie van Onderwijs, Cultuur en Wetenschap
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91719300, 10140)
  • ZonMw
  • European Commission
  • Ministerie van Volksgezondheid, Welzijn en Sport
  • KWF Kankerbestrijding
  • Erasmus Medisch Centrum
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
statins, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, dyslipidemia, anti-inflammatory activity, lipid droplet accumulation, liver organoids, macrophages, inflammatory cytokines, statin prescribing
MeSH terms
Cross-Sectional Studies, Fibrosis, Humans, Liver, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Dyslipidemias, Non-alcoholic Fatty Liver Disease

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