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

Ibrahim Ayada; Laurens A van Kleef; Huai Zhang; Kuan Liu; Pengfei Li; Yasir J Abozaid; Marla Lavrijsen; Harry L A Janssen; Luc J W van der Laan; Mohsen Ghanbari; Maikel P Peppelenbosch; Ming-Hua Zheng; Robert J de Knegt; Qiuwei Pan

doi:10.1016/j.ebiom.2022.104392

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

EBioMedicine. 2023 Jan:87:104392. doi: 10.1016/j.ebiom.2022.104392. Epub 2022 Dec 8.

Authors

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
² Department of Biostatistics and Records Room, Medical Quality Management Office, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
⁴ Department of Epidemiology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
⁵ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Toronto Center for Liver Disease, Toronto General Hospital, University of Toronto, Canada.
⁶ Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
⁷ NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China. Electronic address: zhengmh@wmu.edu.cn.
⁸ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. Electronic address: r.deknegt@erasmusmc.nl.
⁹ Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. Electronic address: q.pan@erasmusmc.nl.

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.

Keywords: General and patient population; Meta-analysis; Metabolic dysfunction; NAFLD treatment; Organoids; Statins.

Publication types

Meta-Analysis

MeSH terms

Cross-Sectional Studies
Dyslipidemias* / metabolism
Fibrosis
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / adverse effects
Liver / metabolism
Non-alcoholic Fatty Liver Disease* / complications
Non-alcoholic Fatty Liver Disease* / etiology

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors