Hypoxia-inducible factor-1α regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis

Copple, Bryan L.; Bai, Shan; Burgoon, Lyle D.; Moon, Jeon Ok

doi:10.1111/j.1478-3231.2010.02347.x

Cited by 139 publications

(129 citation statements)

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“…Our finding that HIF1 regulates cP4H subunits corresponds with previous in vitro studies in different cell types, including fibroblasts and hepatoma cells, which suggest that HIF1 regulates cP4HI and cP4HII expression (Copple et al, 2011;Grimmer et al, 2006;Hofbauer et al, 2003;Takahashi et al, 2000). This raises the possibility that HIF1-mediated regulation of cP4Hs is a broad phenomenon that is not restricted to chondrocytes.…”

Section: Research Articlesupporting

confidence: 89%

“…While cP4HI is the main  subunit in most cell types, in chondrocytes it is cP4HII (Myllyharju, 2003;Myllyharju and Kivirikko, 2004). Previous in vitro studies have raised the possibility that HIF1 may regulate cP4Hs in chondrocytes and other cell types (Copple et al, 2011;Grimmer et al, 2006;Hofbauer et al, 2003;Takahashi et al, 2000). Therefore, the expression of cP4H subunits was first analyzed in chondrocyte primary culture.…”

Section: Hif1 Regulates Cp4h Expression In the Growth Platementioning

confidence: 99%

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HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

2012

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Collagen production is fundamental for the ontogeny and the phylogeny of all multicellular organisms. It depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as a substrate. This dependency is expected to limit collagen production to oxygenated cells. However, during embryogenesis, cells in different tissues that develop under low oxygen levels must produce this essential protein. In this study, using the growth plate of developing bones as a model system, we identify the transcription factor hypoxia-inducible factor 1 α (HIF1α) as a central component in a mechanism that underlies collagen hydroxylation and secretion by hypoxic cells. We show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of extracellular matrix proteins, including collagen type II. Reduced collagen hydroxylation and endoplasmic reticulum stress induction in Hif1a-depleted cells suggests that HIF1α regulates collagen secretion by mediating its hydroxylation and consequently its folding. We demonstrate in vivo the ability of Hif1α to drive the transcription of collagen prolyl 4-hydroxylase, which catalyzes collagen hydroxylation. We also show that, concurrently, HIF1α maintains cellular levels of oxygen, most likely by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. Through this two-armed mechanism, HIF1α acts as a central regulator of collagen production that allows chondrocytes to maintain their function as professional secretory cells in the hypoxic growth plate. As hypoxic conditions occur also during pathological conditions such as cancer, our findings may promote the understanding not only of embryogenesis, but also of pathological processes.

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Section: Research Articlesupporting

confidence: 89%

Section: Hif1 Regulates Cp4h Expression In the Growth Platementioning

confidence: 99%

HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

2012

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“…Apolipoprotein L domain containing 1 (APOLD1) is a new endothelial cell early response protein that may play a role in regulation of endothelial cell signaling and vascular function (Regard et al, 2004). APOLD1 is also found to be upregulated by hypoxia (Copple et al, 2011). Angiopoietin-like 4 (ANGPTL4) gene is induced under hypoxic (low oxygen) conditions in endothelial cells and is the target of peroxisome proliferation activators, which also act as an apoptosis survival factor for vascular endothelial cells (Kim et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Expression profiling analysis of hypoxic pulmonary disease

Zhou

Wang²,

Song³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Exposure of humans to low levels of environmental oxygen results in alveolar hypoxia and normally causes chronic pulmonary hypertension and morphological alterations of precapillary pulmonary vessels. In this study, the microarray dataset GSE11341 was used to identify potential differentially expressed genes related with human lung microvascular endothelial cell hypoxia. In addition, gene ontology term enrichment analysis was performed to explore their underlying functions. In addition, we also investigated the small molecules by comparing with the Connectivity Map. We found that hypoxia samples of 3, 24, and 48 h relative to 0 h displayed 22, 21, and 29 differentially expressed genes, respectively. Among them, six genes (ADM, HMOX1, VEGFA, EGLN3, APOLD1, and ANGPTL4) were closely related to pulmonary microvascular endothelial cell hypoxia response. Three drugs (pindolol, sulfapyridine, and ciclopirox) were selected as candidates to treat hypoxia-related pulmonary diseases. In conclusion, our results provide some underlying drug targets for treatment of hypoxic pulmonary patients.

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“…HIFs are the master regulators of oxygen homeostasis and regulate the expression of many genes involved in glycolysis, glucose transport, and synthesis of inflammatory and proangiogenic cytokines [89][90][91] . The HIF-1α protein is rapidly degraded under normoxic conditions, whereas hypoxia enhances HIF-1α levels by inhibiting its degradation [92][93][94] . HIF-1α has been implicated in many models of liver injury [95] and it has been reported that feeding mice for 4 wk with the Lieber-DeCarli diet increases HIF-1α mRNA, protein, and DNA-binding activity in the liver.…”

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confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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Hypoxia-inducible factor-1α regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis

Cited by 139 publications

References 44 publications

HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development

Expression profiling analysis of hypoxic pulmonary disease

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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