Abstract
Nrf2, a central regulator of the cellular defense against oxidative stress and inflammation, participates in modulating hepatocyte proliferation during liver regeneration. It is not clear, however, whether Nrf2 regulates hepatocyte growth, an important cellular mechanism to regain the lost liver mass after partial hepatectomy (PH). To determine this, various analyses were performed in wild-type and Nrf2-null mice following PH. We found that, at 60 h post-PH, the vast majority of hepatocytes lacking Nrf2 reduced their sizes, activated hepatic progenitor markers (CD133, TWEAK receptor, and trefoil factor family 3), depleted HNF4α protein, and downregulated the expression of a group of genes critical for their functions. Thus, the identity of hepatocytes deficient in Nrf2 was transiently but massively impaired in response to liver mass loss. This event was associated with the coupling of protein depletion of hepatic HNF4α, a master regulator of hepatocyte differentiation, and concomitant inactivation of hepatic Akt1 and p70S6K, critical hepatocyte growth signaling molecules. We conclude that Nrf2 participates in maintaining newly regenerated hepatocytes in a fully differentiated state by ensuring proper regulation of HNF4α, Akt1, and p70S6K during liver regeneration.
Highlights
Nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper region-containing transcription factor, is ubiquitously expressed all over the body, but more predominantly in metabolic organs, including the liver [1]
The data indicate that hepatocytes undergo progressive growth as liver regeneration advances
We found that CD133, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor (Fn14), and trefoil factor family 3 (TFF3) were highly upregulated due to the lack of Nrf2
Summary
Nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper region-containing transcription factor, is ubiquitously expressed all over the body, but more predominantly in metabolic organs, including the liver [1]. The various beneficial effects exerted by the activation of Nrf in detoxification, antioxidation, and anti-inflammation have attracted numerous investigators to study its regulation, modes of action, target genes, and functions in health and disease, especially over the past decade [2,3,4,5]. Upon activation by actin-binding Kelch-like ECH-associated protein 1 (Keap1)-dependent and Keap1-independent mechanisms, Nrf translocates into the nucleus and regulates the transcription of a network of genes involved in various cellular activities, including redox balance, metabolism, proliferation, and apoptosis. Thereby, Nrf is required for maintaining tissue homeostasis.
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