Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage

Anavi, Sarit; Hahn-Obercyger, Michal; Madar, Zecharia; Tirosh, Oren

doi:10.1016/j.freeradbiomed.2014.03.007

Cited by 50 publications

(44 citation statements)

References 33 publications

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“…23,24 Consistent with previous findings, in the current study HIF-1α was significantly increased in HCD-fed WT mice and was higher than in iNOS-deficient mice (Figure 3a). The elevated HIF-1 induction in HCD-fed WT mice was concomitant with a greater increase in the expression of profibrotic genes, ie, platelet-derived growth factor (PDGF)-A, PDGF-B, fibroblast growth factor-2 (FGF-2), and a trend toward higher plasminogen activator inhibitor-1 (PAI-1) expression, all of which were previously shown to be regulated in HIF-1α-dependent manner (Figure 3b-e).…”

Section: Effects Of Hcd On Hif-1 Activation In Wt and Inos-deficient supporting

confidence: 93%

“…This result is in accordance with our previous findings in which cholesterol induced the HIF-1 pathway in the liver and was iNOS dependant. 23,24 Recent data suggest an important role for HIF-1 in the pathogenesis of fibrotic diseases, including liver fibrosis. Indeed, many genes under the regulation of HIF-1 have been implicated in the pathogenesis of liver fibrosis as well as in ECM modifications.…”

Section: Discussionmentioning

confidence: 99%

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The role of iNOS in cholesterol-induced liver fibrosis

Anavi

Eisenberg-Bord

Hahn-Obercyger

et al. 2015

Laboratory Investigation

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Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1a stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.Laboratory Investigation (2015) 95, 914-924;

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Section: Effects Of Hcd On Hif-1 Activation In Wt and Inos-deficient supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

The role of iNOS in cholesterol-induced liver fibrosis

Anavi

Eisenberg-Bord

Hahn-Obercyger

et al. 2015

Laboratory Investigation

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“…HIF-1a is a ubiquitous oxygen-sensitive protein that regulates transcription of genes involved in metabolic adaptation, energy conservation, angiogenesis, and cell survival in response to cellular hypoxia and nonhypoxic stimuli like cholesterol overload (21). Inappropriate HIF-1a activation following such stimuli as chronic intermittent hypoxia and cholesterol overload has been found to be involved in NASH pathogenesis (22,62), whereas chronic hypoxia has been implicated in renal injury in early diabetic and obesity-related CKD (63,64) (Fig.…”

Section: Role Of Cellular Energy Oxygen and Nutrient Sensorsmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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“…2). However, it is also possible that age-dependent HIF1a activation is triggered by progressive oxidative stress or simply by lipid accumulation, both of which have been reported to activate HIF1a independently of oxygen availability [35][36][37] (Fig. 2).…”

Section: Age-dependent White Adipocyte Hif1a Expressionmentioning

confidence: 99%

“…38,39 Furthermore, a recent study has shown that cholesterol can lead to HIF1a activation via ROS generation. 37 Finally, fat accumulation in HFD-fed mice can also promote HIF1a accumulation through free fatty acid-induced mitochondrial uncoupling and increased oxygen consumption. 8 It is however unlikely that this latter mechanism is predominant in age-dependent WAT expansion since mitochondrial oxygen consumption is reduced 10 and it is anticipated that the supply of free fatty acids to white adipocytes is much lower than that in HFD models.…”

Section: Age-dependent White Adipocyte Hif1a Expressionmentioning

confidence: 99%

Age-dependent obesity and mitochondrial dysfunction

Soro-Arnáiz

Aragonés

2017

Adipocyte

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Aging is associated with progressive visceral white adipose tissue (WAT) expansion both in human and mouse. Importantly, WAT enlargement is initiated early in life, suggesting that molecular mechanisms underlying age-dependent obesity are activated at early stages of lifetime. Our recent study found that age-dependent obesity was associated with a specific decline in mitochondrial complex IV activity, which leads to reduced fatty acid oxidation and subsequent adipocyte hypertrophy. At the molecular level, global mitochondrial complex IV inhibition was driven by hypoxia-inducible factor-1a (HIF1a)-mediated repression of some of its key subunits, including cytochrome c oxidase 5b (Cox5b). In this commentary, we compare age-dependent WAT responses with those observed in the high fat diet model of extreme obesity. Furthermore, we discuss the potential scenarios that could initiate age-dependent WAT expansion as well as the mechanisms by which HIF1a could be activated in WAT.

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Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage

Cited by 50 publications

References 33 publications

The role of iNOS in cholesterol-induced liver fibrosis

The role of iNOS in cholesterol-induced liver fibrosis

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Age-dependent obesity and mitochondrial dysfunction

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