Crosstalk of HNF4 α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids

Abstract

The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver. There have been a few reviews on the regulation of drug metabolism, lipid metabolism, cell proliferation, and inflammation by HNF4α. However, the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered. Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α, and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

“…The HNF4A gene is composed of 12 exons and driven by two separated P1 and P2 promoters . Overall nine transcriptional variants are generated via alternative splicing . Currently, HNF4α1‐3 and HNF4α7‐9 are experimentally verified P1 and P2 products.…”

Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans

“…HNF4α functions as a transcription factor, and nuclear localization is required for activity. ( 13‐20,22,23,25,34,35 ) Therefore, we performed immunohistochemistry and western blot on hepatocytes from diseased liver specimens to determine the location of HNF4α and to correlate expression with hepatic decompensation. About 78% of hepatocytes from livers with terminal liver failure showed only cytoplasm expression or cytoplasm and weak nuclear expression of HNF4α, whereas normal human livers displayed 75% of hepatocytes with strong nuclear localization of HNF4α (Fig.…”

“…Because the function and stability of HNF4α are regulated by a number of posttranslational modifiers, ( 14‐23 ) and because its nuclear localization is critical to its activity, we performed an in silico analysis to evaluate which modifiers regulate HNF4α localization. We found that adenosine monophosphate–activated protein kinase α (AMPKα) activation controls HNF4α transcription.…”

“…( 13‐15,17‐21,23,25 ) Alterations in HNF4α expression have been described in hepatocellular carcinoma (HCC), hepatitis B, hepatitis C, alcohol‐mediated hepatitis and cirrhosis, as well as NASH. ( 13‐15,17‐21,23,25,46 ) In an animal model of terminal chronic liver failure, HNF4α expression was found to be severely reduced, and restoration of HNF4 expression using gene therapy resulted in normalization of hepatocyte function. ( 12 ) To assess whether this observation applies to humans, we studied liver‐enriched transcription factor expression in the livers of a large cohort of patients with decompensated liver function.…”

“…HNF4α is a transcription factor that plays a critical role in liver organogenesis and hepatocyte function in the mature liver, ( 12,13 ) and its expression and function are regulated at multiple levels. ( 14‐23 ) It must be expressed in the nucleus to function properly; therefore, we analyzed the signaling pathways involved in nuclear localization of HNF4α in hepatocytes isolated from explanted human livers with decompensated function. In this analysis involving a significantly smaller cohort of patients, we were able to demonstrate that decompensated livers have significantly lower expression of nuclear HNF4α and higher expression of cytoplasmic HNF4α when compared with normal controls and correlated with low levels of cMET and phosphorylated AKT (protein kinase B).…”