Hepatocyte Expression of Serum Response Factor Is Essential for Liver Function, Hepatocyte Proliferation and Survival, and Postnatal Body Growth in Mice

Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Hepatology (Impact Factor: 11.06). 05/2009; 49(5):1645-54. DOI: 10.1002/hep.22834
Source: PubMed


Serum response factor (SRF) is a transcription factor that binds to a CarG box motif within the serum response element of genes that are expressed in response to mitogens. SRF plays essential roles in muscle and nervous system development; however, little is known about the role of SRF during liver growth and function. To examine the function of SRF in the liver, we generated mice in which the Srf gene was specifically disrupted in hepatocytes. The survival of mice lacking hepatic SRF activity was lower than that of control mice; moreover, surviving mutant mice had lower blood glucose and triglyceride levels compared with control mice. In addition, Srf(loxP/loxP)AlfpCre mice were smaller and had severely depressed levels of serum insulin-like growth factor 1 (IGF-1). Srf-deficient livers were also smaller than control livers, and liver cell proliferation and viability were compromised. Gene array analysis of SRF depleted livers revealed a reduction in many messenger RNAs, including those encoding components of the growth hormone/IGF-1 pathway, cyclins, several metabolic regulators, and cytochrome p450 enzymes. Conclusion: SRF is essential for hepatocyte proliferation and survival, liver function, and control of postnatal body growth by regulating hepatocyte gene expression.

Download full-text


Available from: Ravi Misra, May 06, 2014
  • Source
    • "To do so, human and murine liver tissues with and without steatosis were triple stained for the nuclear markers Ki67, HNF4α and DAPI. HNF4α has previously been demonstrated to specifically stain hepatpatocytes in the liver [17]. The overall number of proliferating Ki67 positive cells as a percentage of total number of DAPI positive cells as well as the percentage of co-positive Ki67/HNFα proliferating hepatocytes vs total HNF4a positive hepatocytes were counted and quantified per field. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonalchoholic fatty liver disease (NAFLD) is a problem of increasing prevalence and clinical significance worldwide and is associated with increased risk of development of end stage liver disease and cirrhosis, and can be complicated by hepatocellular carcinoma (HCC). NAFLD is characterized by physical and molecular changes in the liver microenvironment which include an influx of inflammatory cell populations, fibrosis, changes in gene expression, and cytokine production. To better understand changes to the liver in the setting of steatosis, we used a murine model of diet induced hepatic steatosis and corroborated our results with human patient samples of NAFLD. Among the cellular changes, we identified a significant increase in hepatocellular proliferation in the setting of steatosis as compared to controls. Analysis of inflammatory cell populations revealed increased infiltration of CD11b positive myeloid and CD3 positive lymphocytic cell populations in steatotic livers compared to normal livers. Resident Kupffer cells of the liver comprise the largest percentage of these myeloid cells and appear to be responsible for important cytokine alterations impacting proliferation of cells in the liver microenvironment. Significant alterations in cytokine profiles in the plasma and liver tissue lysates from normal and steatotic mice were detected including leptin, CXCL1, CXCL2, and CXCL16 that were further shown to directly increase hepatocyte proliferation in vitro. This increased hepatocellular proliferation and turnover in the setting of steatosis may play important roles in the progression and complications of NAFLD.
    Full-text · Article · Sep 2013 · PLoS ONE
  • Source
    • "In addition to cell differentiation, SRF has been implicated in cell survival of various cell types including hepatocytes [2], thymocytes [3], heart cells [4], and during embryogenesis [5]. In embryonic stem cells lacking SRF apoptosis was strongly upregulated [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor SRF (serum response factor) mediates neuronal survival in vitro. However, data available so far suggest that SRF is largely dispensable for neuron survival during physiological brain function. Here, we demonstrate that upon neuronal injury, that is facial nerve transection, constitutively-active SRF-VP16 enhances motorneuron survival. SRF-VP16 suppressed active caspase 3 abundance in vitro and enhanced neuron survival upon camptothecin induced apoptosis. Following nerve fiber injury in vitro, SRF-VP16 improved survival of neurons and re-growth of severed neurites. Further, SRF-VP16 enhanced immune responses (that is microglia and T cell activation) associated with neuronal injury in vivo. Genome-wide transcriptomics identified target genes associated with axonal injury and modulated by SRF-VP16. In sum, this is a first report describing a neuronal injury-related survival function for SRF.
    Full-text · Article · Apr 2012 · Journal of Neuroinflammation
  • Source
    • "Secondly, SRF emerges as transcriptional regulator of many genes encoding components of insulin or insulin growth factor (IGF) signaling in neurons and non-neuronal cells. These genes include the insulin gene (Sarkar et al., 2011), Igf1 (Charvet et al., 2006; Sun et al., 2009), and, e.g., Ctgf, a protein harboring an IGF binding domain (Stritt et al., 2009). Such SRF-mediated control of insulin/IGF regulation in neurons was also demonstrated to affect neighboring cells, i.e., oligodendrocytes, in a paracrine manner (Stritt et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, the transcription factor serum response factor (SRF) was shown to contribute to various physiological processes linked to neuronal motility. The latter include cell migration, axon guidance, and, e.g., synapse function relying on cytoskeletal dynamics, neurite outgrowth, axonal and dendritic differentiation, growth cone motility, and neurite branching. SRF teams up with myocardin related transcription factors (MRTFs) and ternary complex factors (TCFs) to mediate cellular actin cytoskeletal dynamics and the immediate-early gene (IEG) response, a bona fide indicator of neuronal activation. Herein, I will discuss how SRF and cofactors might modulate physiological processes of neuronal motility. Further, potential mechanisms engaged by neurite growth promoting molecules and axon guidance cues to target SRF's transcriptional machinery in physiological neuronal motility will be presented. Of note, altered cytoskeletal dynamics and rapid initiation of an IEG response are a hallmark of injured neurons in various neurological disorders. Thus, SRF and its MRTF and TCF cofactors might emerge as a novel trio modulating peripheral and central axon regeneration.
    Full-text · Article · Dec 2011 · Frontiers in Molecular Neuroscience
Show more