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

Joint Authors

Fernández-Checa, José C.
Tirosh, Oren
Kaminsky-Kolesnikov, Yula
Rauchbach, Einat
Abu-Halaka, Diana
Hahn, Michal
García-Ruiz, Carmen
Madar, Zecharia

Source

Oxidative Medicine and Cellular Longevity

Issue

Vol. 2020, Issue 2020 (31 Dec. 2020), pp.1-18, 18 p.

Publisher

Hindawi Publishing Corporation

Publication Date

2020-05-26

Country of Publication

Egypt

No. of Pages

18

Main Subjects

Biology

Abstract EN

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-1α, 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-1α 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.

American Psychological Association (APA)

Kaminsky-Kolesnikov, Yula& Rauchbach, Einat& Abu-Halaka, Diana& Hahn, Michal& García-Ruiz, Carmen& Fernández-Checa, José C.…[et al.]. 2020. Cholesterol Induces Nrf-2- and HIF-1α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis. Oxidative Medicine and Cellular Longevity،Vol. 2020, no. 2020, pp.1-18.
https://search.emarefa.net/detail/BIM-1204837

Modern Language Association (MLA)

Kaminsky-Kolesnikov, Yula…[et al.]. Cholesterol Induces Nrf-2- and HIF-1α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis. Oxidative Medicine and Cellular Longevity No. 2020 (2020), pp.1-18.
https://search.emarefa.net/detail/BIM-1204837

American Medical Association (AMA)

Kaminsky-Kolesnikov, Yula& Rauchbach, Einat& Abu-Halaka, Diana& Hahn, Michal& García-Ruiz, Carmen& Fernández-Checa, José C.…[et al.]. Cholesterol Induces Nrf-2- and HIF-1α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis. Oxidative Medicine and Cellular Longevity. 2020. Vol. 2020, no. 2020, pp.1-18.
https://search.emarefa.net/detail/BIM-1204837

Data Type

Journal Articles

Language

English

Notes

Includes bibliographical references

Record ID

BIM-1204837