Hypoxia‐Inducible Factor‐1 Is a Determinant of Lobular Structure and Oxygen Consumption in the Liver

Tsukada, Kosuke; Tajima, T; Hori, Shutaro; Matsuura, Tomomi; Johnson, Randall S.; Goda, Nobuhito; Suematsu, Makoto

doi:10.1111/micc.12033

Cited by 15 publications

(13 citation statements)

References 27 publications

(29 reference statements)

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“…The importance of HIF transcription factors for structural maintenance of the liver is exemplified in studies from mice with hepatocyte-specific HIF-1α deficiency. Those mice displayed an extension of hepatic lobules, an enhanced lobular oxygen consumption and an increased content of mtDNA [44]. Further, HIFs regulate major metabolic liver functions, and in particular studies in which either ARNT or the two HIFα subunits were deleted supported this.…”

Section: Hypoxia-inducible Transcription Factors (Hifs)mentioning

confidence: 86%

Metabolic zonation of the liver: The oxygen gradient revisited

Kietzmann

2017

Redox Biology

390

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The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function.

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Section: Hypoxia-inducible Transcription Factors (Hifs)mentioning

confidence: 86%

Metabolic zonation of the liver: The oxygen gradient revisited

Kietzmann

2017

Redox Biology

390

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“…HIF-1α is degraded under normal oxygen stress and undergoes ubiquitination. However, degradation is suppressed when the cells are exposed to hypoxic condition; as a result, HIF-1α is amplified rapidly and accumulates in cells [25]. …”

Section: Discussionmentioning

confidence: 99%

Polymorphism in the Hypoxia-Inducible Factor 1alpha Gene May Confer Susceptibility to LDD in Chinese Cohort

Lin¹,

Wang²,

Wang³

et al. 2013

PLoS ONE

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ObjectiveThis study aimed to investigate whether or not hypoxia-inducible factor-1α (HIF-1α) gene variants are associated with the susceptibility and clinical characteristics of lumbar disc degeneration (LDD).MethodsWe examined 320 patients with LDD and 447 gender- and age-matched control subjects. We also determined the HIF-1α gene variants, including C1772T (P582S) and G1790A (A588T) polymorphisms.ResultsSignificant differences were observed in allelic and genotypic distributions of 1790 A > G polymorphisms between LDD cases and control subjects. Logistic regression revealed that 1790 AA genotypes indicated a protective effect against the development of LDD. The HIF-1α 1790 A > G polymorphisms also affected the severity of LDD as evaluated based on the modified Japanese Orthopedic Association (mJOA) scores. The 1790 AA genotype carriers exhibited significantly lower mJOA scores than AG and GG carriers. C1772T did not show any association with the risk and severity of LDD.ConclusionOur study suggested that HIF-1α 1790 A > G polymorphisms may be used as a molecular marker to determine the susceptibility and severity of LDD.

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“…HIF1α could upregulate expressions of Nanog and Oct4 and is implicated in regulating mitochondrial functions and to promote a metabolic shift toward glycolysis in ESCs and iPSCs . Furthermore, HIF1α is also implicated in suppression of PGC1α expression in different cellular contexts . Therefore, we tested HIF1α protein expression in PKCλ/ιKD ESCs.…”

Section: Resultsmentioning

confidence: 99%

“…The other interesting aspect of this study is direct transcriptional regulation of PGC1α by HIF1α. Several previous studies have shown that, depending on a cellular context, hypoxia could modulate PGC1α expression both in a positive and a negative fashion. However, PGC1α induction by hypoxia does not require HIF1α activity .…”

Section: Discussionmentioning

confidence: 99%

Regulation of Mitochondrial Function and Cellular Energy Metabolism by Protein Kinase C-λ/ι: A Novel Mode of Balancing Pluripotency

Mahato¹,

Home

Rajendran

et al. 2014

Stem Cells

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Pluripotent stem cells (PSCs) contain functionally immature mitochondria and rely upon high rates of glycolysis for their energy requirements. Thus, altered mitochondrial function and promotion of aerobic glycolysis is key to maintain and induce pluripotency. However, signaling mechanisms that regulate mitochondrial function and reprogram metabolic preferences in self-renewing vs. differentiated PSC populations are poorly understood. Here, using murine embryonic stem cells (ESCs) as a model system, we demonstrate that atypical protein kinase C isoform, PKC lambda/iota (PKCλ/ι), is a key regulator of mitochondrial function in ESCs. Depletion of PKCλ/ι in ESCs maintains their pluripotent state as evident from germline offsprings. Interestingly, loss of PKCλ/ι in ESCs leads to impairment in mitochondrial maturation, organization and a metabolic shift toward glycolysis under differentiating condition. Our mechanistic analyses indicate that a PKCλ/ι-HIF1α-PGC1α axis regulates mitochondrial respiration and balances pluripotency in ESCs. We propose that PKCλ/ι could be a crucial regulator of mitochondrial function and energy metabolism in stem cells and other cellular contexts.

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Hypoxia‐Inducible Factor‐1 Is a Determinant of Lobular Structure and Oxygen Consumption in the Liver

Abstract: Our results suggest that constitutive expression of HIF-1α in hepatocytes acts as a determinant of hepatic lobular structure and oxygen consumption by changing mitochondrial contents.

Cited by 15 publications

References 27 publications

Metabolic zonation of the liver: The oxygen gradient revisited

Metabolic zonation of the liver: The oxygen gradient revisited

Polymorphism in the Hypoxia-Inducible Factor 1alpha Gene May Confer Susceptibility to LDD in Chinese Cohort

Regulation of Mitochondrial Function and Cellular Energy Metabolism by Protein Kinase C-λ/ι: A Novel Mode of Balancing Pluripotency

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