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Cited by 39Liver physiology and pathologyLiver Disease Diagnosis and TreatmentDrug-Induced Hepatotoxicity and Protection

Cholesterol Induces Nrf-2- and HIF-1 α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis

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Kaminsky-Kolesnikov, Yula, Rauchbach, Einat, Abu-Halaka, Diana, Hahn, Michal, García-Ruiz, Carmen, Fernandez-Checa, Jose C., Madar, Zecharia, Tirosh, Oren·2020·Oxidative Medicine and Cellular Longevity
DOI 10.1155/2020/5393761PMC PMC7271232
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Abstract

Nonalcoholic steatohepatitis (NASH) is currently one of the most common liver diseases worldwide. The toxic effects of lipids and bile acids contribute to NASH. The regenerative pathway in response to damage to the liver includes activation of the inflammatory process and priming of hepatocytes to proliferate to restore tissue homeostasis. However, the effects of cholesterol on bile acid toxicity, inflammation, and fibrosis remain unknown. We have used two mouse models of bile acid toxicity to induce liver inflammation and fibrosis. A three-week study was conducted using wild-type mice receiving an atherogenic diet (1% (w/w) cholesterol and 0.5% (w/w) cholic acid) and its separate constituents. Mdr2-/- mice were fed a high-cholesterol-enriched diet or standard AIN-93 diet for 6 weeks. We measured serum transaminase levels to assess liver tissue necrosis and fibrosis; iNOS, SAA1, SAA2, and F4/80 levels to determine liver inflammation; PCNA and HGF levels to evaluate proliferative response; and Nrf-2, HIF-1 α, and downstream gene expression to establish protective responses. In both studies, high bile acid levels increased serum transaminases and liver fibrosis, whereas cholesterol supplementation attenuated these effects. Cholesterol supplementation activated survival and the robustness of HIF-1 α and Nrf-2 gene expression in hepatocytes, induced liver inflammation and hepatocyte proliferation, and inhibited stellate cell hyperplasia and fibrosis. In conclusion, our data show for the first time that cholesterol intake protects against bile acid liver toxicity. The balance between hepatic cholesterol and bile acid levels may be of prognostic value in liver disease progression and trajectory.

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  • Exogenous cholesterol activates HIF-1α and Nrf-2 pathways, which enhance hepatocyte proliferation and survival.

    “The addition of exogenous cholesterol activates Hypoxia-Inducible Factor 1-alpha (HIF-1α) and Nuclear Factor Erythroid 2-Related Factor 2 (Nrf-2) pathways, which enhance hepatocyte proliferation and survival[69].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [69]

  • Cholesterol metabolism and bile acid signaling play key roles in liver regeneration.

    “Studies have demonstrated that cholesterol metabolism and bile acid signaling play key roles in LR.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [69]

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Authors
Kaminsky-Kolesnikov, Y., Rauchbach, E., Abu-Halaka, D., Hahn, M., García-Ruiz, C., Fernandez-Checa, J. C., Madar, Z., & Tirosh, O.
Affiliations
  • Institute of Biochemistry, Food Science, And Nutrition, RHS Faculty of Agriculture Food and Environment, The Hebrew University of Jerusalem, Israel
  • Hebrew University of Jerusalem (IL)
  • Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
Corresponding author
Tirosh, Oren
ORCID
Venue
Oxidative Medicine and Cellular Longevity
Publisher
Wiley
Published
2020-05-26
Volume
2020
Pages
1-18
ISSN
  • 1942-0994 (ISSN-L)
  • 1942-0900
DOI
10.1155/2020/5393761
PMC
PMC7271232
OpenAlex
W3031612395
Cited by
39
References
8
Citations by year
2026: 2 · 2025: 5 · 2024: 7 · 2023: 13 · 2022: 7 · 2021: 5
FWCI
3.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Israel Science Foundation (371/12)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
cholesterol, bile acid toxicity, nonalcoholic steatohepatitis, liver fibrosis, hepatocyte proliferation, liver regeneration, Nrf2, HIF-1α, hepatocyte viability, liver inflammation, hepatic stellate cells, Mdr2 knockout mice, atherogenic diet, cholic acid, hepatoprotection
MeSH terms
Animals, Antioxidants, Bile Acids and Salts, Body Weight, Cholesterol, Disease Models, Animal, Feeding Behavior, Inflammation, Liver, Liver Cirrhosis, Liver Regeneration, Male, Mice, Inbred C57BL, Biomarkers, Hepatocytes, Cell Proliferation, NF-E2-Related Factor 2, Hypoxia-Inducible Factor 1, alpha Subunit, Non-alcoholic Fatty Liver Disease

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