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Role of HNF4alpha-cMyc interaction in liver regeneration after partial hepatectomy
Kotulkar, Manasi Paine-Cabrera, Diego Venneman, Kaitlyn Apte, Udayan
Kotulkar, Manasi
Paine-Cabrera, Diego
Venneman, Kaitlyn
Apte, Udayan
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4α) is a highly conserved member of the nuclear receptor expressed at high levels in hepatocytes. HNF4α is important for normal liver development and the maintenance of hepatic differentiation (1). HNF4α regulates various metabolic processes, including bile acid and coagulation factor synthesis, lipid, glucose and amino acid metabolism, and expression of several drug metabolism genes (2–5). Recent studies have shown that HNF4α also regulates hepatocyte proliferation (6). Deletion of HNF4α results in increased spontaneous hepatocyte proliferation without liver injury, and it also promotes carcinogen-induced hepatocellular carcinoma (6). HNF4α negatively regulates several pro-mitogenic genes, including but not limited to the proto-oncogene cMyc (7).
The liver has an exceptional ability to regenerate following drug-and diet-induced liver injury and surgical resection (8). Liver regeneration is a highly regulated process that involves cell proliferation and tissue remodeling. Partial hepatectomy (PHX) is the most common model for studying liver regeneration, in which approximately 70% of the liver is surgically removed and the remnant liver is allowed to regenerate (9). After PHX, hepatocytes leave the quiescence phase and start proliferating to contribute to the regeneration process. This model is clinically significant because PHX is a common therapy for several chronic liver diseases and is also the basis for successful living donor liver transplantation (10). Furthermore, understanding the mechanisms of the initiation and termination of hepatocyte proliferation is crucial because excessive proliferation can lead to carcinogenesis.
Previous studies in our laboratory investigated the role of HNF4α in regulating liver regeneration after PHX (7). Our studies revealed that HNF4α is essential for the termination of liver regeneration. Other studies from our laboratory investigated the role of HNF4α-cMyc interaction in liver regeneration after drug-and diet-induced liver injury. We found that after acetaminophen-induced acute induced liver injury, HNF4α contributes to regeneration by downregulating the expression of cMyc and supports cytoprotection by inducing Nrf2 activity (11). During choline deficient and ethionine supplemented (CDE) diet-induced chronic liver injury, HNF4α protects against injury, which is exacerbated by cMyc (12). Both the acetaminophen overdose and CDE diet feeding models are different from PHX in the context of liver injury, inflammation, and regenerative cell type. In this study, we investigated the role of HNF4α-cMyc interaction in the regulation of liver regeneration after PHX, a model with significantly less inflammation.
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A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.
Date
2024-07-30
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Frontiers
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Kotulkar Manasi , Paine-Cabrera Diego , Venneman Kaitlyn , Apte Udayan , Role of HNF4alpha-cMyc interaction in liver regeneration after partial hepatectomy, Frontiers in Endocrinology, VOLUME=15, 2024, https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1404318, 0.3389/fendo.2024.1404318, 664-2392