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Cited by 18Liver physiology and pathologyDrug Transport and Resistance MechanismsCholesterol and Lipid Metabolism

Redundant Functions of ERK1 and ERK2 Maintain Mouse Liver Homeostasis Through Down‐Regulation of Bile Acid Synthesis

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Cingolani, Francesca, Liu, Yunshan, Shen, Yang, Wen, Jing, Farris, Alton B., Czaja, Mark J.·2022·Hepatology Communications
DOI 10.1002/hep4.1867PMC PMC9035584
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Abstract

Activation of extracellular signal–regulated kinase (ERK) 1/2 promotes hepatocyte proliferation in response to growth stimuli, but whether constitutive hepatocyte ERK1/2 signaling functions in liver physiology is unknown. To examine the role of ERK1/2 in hepatic homeostasis, the effects of a knockout of Erk1 and/or Erk2 in mouse liver were examined. The livers of mice with a global Erk1 knockout or a tamoxifen‐inducible, hepatocyte‐specific Erk2 knockout were normal. In contrast, Erk1/2 double‐knockout mice developed hepatomegaly and hepatitis by serum transaminases, histology, terminal deoxynucleotide transferase‐mediated deoxyuridine triphosphate nick end‐labeling, and assays of hepatic inflammation. Liver injury was associated with biochemical evidence of cholestasis with increased serum and hepatic bile acids and led to hepatic fibrosis and mortality. RNA sequencing and polymerase chain reaction analysis of double‐knockout mouse livers revealed that the rate‐limiting bile acid synthesis gene Cyp7a1 (cholesterol 7α‐hydroxylase) was up‐regulated in concert with decreased expression of the transcriptional repressor short heterodimer partner. Elevated bile acids were the mechanism of liver injury, as bile acid reduction by SC‐435, an inhibitor of the ileal apical sodium–dependent bile acid transporter, prevented liver injury. Conclusion: Constitutive ERK1 and ERK2 signaling has a redundant but critical physiological function in the down‐regulation of hepatic bile acid synthesis to maintain normal liver homeostasis.

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Cited by

Sorted by citations

Authors
Cingolani, F., Liu, Y., Shen, Y., Wen, J., Farris, A. B., & Czaja, M. J.
Affiliations
Emory University (US)
Corresponding author
Czaja, Mark J.
ORCID
Venue
Hepatology Communications
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-12-22
Volume
6
Issue
5
Pages
980-994
ISSN
2471-254X (ISSN-L)
DOI
10.1002/hep4.1867
PMC
PMC9035584
OpenAlex
W4200142293
Cited by
18
References
0
Citations by year
2026: 1 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 3
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology Communications (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Emory University
  • Shire
  • School of Medicine, Emory University
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK044234)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
ERK signaling, bile acid synthesis, liver homeostasis, hepatocyte proliferation, hepatomegaly, cholestasis, liver fibrosis, CYP7A1, ileal bile acid transporter, hepatocyte-specific knockout, liver injury
MeSH terms
Animals, Bile Acids and Salts, Homeostasis, Liver, Down-Regulation, Mice, Knockout, MAP Kinase Signaling System, Mice

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