ArticleHepatology communications2022
Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol.
Article in Hepatology communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.Nature genetics · 2023Pooled it
- Role of PCSK9 in hallmarks of cancer: From mechanisms to interventions (Review).Oncology letters · 2026Review
- Dyslipidaemia and hepatic steatosis: mechanisms and implications for lipid-lowering therapy.Nature reviews. Cardiology · 2026Review
- Association of PCSK9 inhibitors versus statins with cancer incidence: a target trial emulation.Cardio-oncology (London, England) · 2026Article
- Heart-liver co-management: epidemiology, mechanisms, and novel therapeutic approaches for metabolic dysfunction-associated steatotic liver disease and coronary artery disease.Frontiers in cardiovascular medicine · 2026Review
- Targeting intramyocellular lipids to improve aging muscle function.Lipids in health and disease · 2025Review
- Article
- [Strategies of statins for the prevention and treatment of hepatocellular carcinoma].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025Review
- PCSK9 Manipulates Lipid Metabolism and the Immune Microenvironment in Cancer.OncoTargets and therapy · 2025Review
- Recent Overview of Protein Palmitoylation and Profiling Methodologies.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Damaging mutations in liver X receptor-α are hepatotoxic and implicate cholesterol sensing in liver health.Nature metabolism · 2024Article
- Unlocking Cholesterol Metabolism in Metabolic-Associated Steatotic Liver Disease: Molecular Targets and Natural Product Interventions.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Article
- Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.Signal transduction and targeted therapy · 2024Review
- Anti-PCSK9 Treatment Attenuates Liver Fibrosis via Inhibiting Hypoxia-Induced Autophagy in Hepatocytes.Inflammation · 2023Article
- Intestinal Pgc1α ablation protects from liver steatosis and fibrosis.JHEP reports : innovation in hepatology · 2023Article
- The Anti-Thrombotic Effects of PCSK9 Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose.American journal of physiology. Gastrointestinal and liver physiology · 2023Article
- The evolving landscape of PCSK9 inhibition in cancer.European journal of pharmacology · 2023Review
- Genetic deletion or pharmacologic inhibition of the Nlrp3 inflammasome did not ameliorate experimental NASH.Journal of lipid research · 2023Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Proprotein convertase subtilisin/kexin type 9 (Pcsk9) binds to hepatic low-density lipoprotein receptor (LDLR) and induces its internalization and degradation. Pcsk9 inhibition increases LDLR expression by hepatocytes, which causes increased uptake of circulating LDL, thereby reducing plasma LDL-cholesterol. However, by increasing the uptake of LDL by the liver, Pcsk9 inhibition increases the exposure of the liver to cholesterol, which may result in higher risk of steatohepatitis and ever carcinogenesis. We compared Pcsk9-/- knockout (KO) mice and appropriate wild-type (WT) controls of the same strain assigned to a high-fat (15%, wt/wt) diet for 9 months supplemented with 0.25%, 0.5%, or 0.75% dietary cholesterol. Pcsk9 KO mice on a high-fat, high-cholesterol diet exhibited higher levels of hepatic free cholesterol loading and hepatic cholesterol crystallization than their WT counterparts. Pcsk9 KO mice developed crown-like structures of macrophages surrounding cholesterol crystal-containing lipid droplets and hepatocytes, exhibited higher levels of apoptosis, and developed significantly more hepatic inflammation and fibrosis consistent with fibrosing steatohepatitis, including 5-fold and 11-fold more fibrosis at 0.5% and 0.75% dietary cholesterol, respectively. When injected with diethylnitrosamine, a hepatic carcinogen, early-in-life Pcsk9 KO mice were more likely to develop liver cancer than WT mice. Conclusion: Pcsk9 KO mice on high-cholesterol diets developed increased hepatic free cholesterol and cholesterol crystals and fibrosing steatohepatitis with a higher predisposition to liver cancer compared with WT mice. Future studies should evaluate whether patients on long-term treatment with anti-PSCK9 monoclonal antibodies are at increased risk of hepatic steatosis, steatohepatitis or liver cancer, while accounting for concurrent use of statins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.