Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Zheng, Yi; Qu, Hua; Xiong, Xin; Wang, Yuren; Liu, Xiufei; Zhang, Linlin; Liao, Xiaoyu; Liao, Qian; Sun, Zheng; Ouyang, Qin; Yang, Gangyi; Zhu, Zhiming; Xu, Jing; Wang, Cong-Yi

doi:10.1002/hep.30507

Cited by 38 publications

(41 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MPT can be induced by calcium overload, oxidative stress, and the accumulation of some toxic endobiotics like bile acids, the conditions of which are implicated in many kinds of diseases including cholesteric liver failure, ischemic reperfusion injury, and neurologic diseases (Gandhi et al, 2009; Izzo et al, 2016; Zheng et al, 2019). MPT-driven cell death was previously referred as regulated necrosis without clear mechanism.…”

Section: Discussionmentioning

confidence: 99%

Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Cao

Hao

2020

Preprint

View full text Add to dashboard Cite

HighlightsBile acids trigger caspase-4/11 and GSDME dependent pyroptosis Caspase-4/11 is a general sensor of mitochondrial permeability transition (MPT) MPT drives Apaf-1/capase-4 pryoptosome assembly Caspase-11 and GSDME mediated pyroptosis underlies cholesteric liver damage eTOC Blurb Persistent mitochondrial permeability transition elicited by bile acids, calcium overload and specifically ANT1 activators drives assembly of Apaf-1-capase-4/11 pyroptosome triggering GSDME dependent pryroptosis. 3 SUMMARY Caspase-4 directly senses and is activated by cytosolic LPS in conditions of pathogen infection. It is unclear whether and how caspase-4 detects host derived factors for triggering pyroptosis. Here we show that mitochondrial permeability transition (MPT) promotes the assembly of a protein complex comprised of Apaf-1 and caspase-4 (caspase-11 in mice)， defined herein as pyroptosome, for the execution of facilitated pyroptosis. MPT induced by bile acids and calcium overload, and specifically by an adenine nucleotide translocator 1 (ANT1) activator, triggered pyroptosome assembly. Different from the direct cleavage of GSDMD by LPS-activated caspase-4, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby gasdermin E (GSDME) to induce pyroptosis. Caspase-11 initiated and GSDME executed pyroptosis underlies cholesteric liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed lights on understanding how cells execute pyroptosis under sterile conditions.contrast, knockout of caspase-1 exerted little influence on bile acid induced cell death and IL-1α secretion, confirming that the featured cell death triggered by bile acid is caspase-11 mediated pyroptosis (Figures 1I-L). Cytotoxicity of bile acids at concentrations higher than 400 μ M might be partially related to their detergent effects (Benedetti et al., 1997). We further demonstrated that equivalent amount of SDS to that of 200 μ M bile acid was unable to activate caspases, excluding the possibility of detergent effects being involved in caspase activation by bile acids (Figures S1J-M). Neither RIP1 inhibitor nor MLKL inhibitor blocked bile acids induced cell death, suggesting that bile acids induced cell death was not necroptosis (Figures S1N and S1O). Moreover, our previous results excluded TLR4 dependence of bile acids function (Hao et al., 2017) and the assay here further verified that bile acids applied as well as cell cultures were free of LPS contamination and bile acids were tested without LPS priming for all experiments performed in this study (STAR Methods).

show abstract

Section: Discussionmentioning

confidence: 99%

Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Cao

Hao

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Wang et al (2018) found good evidence in HFD-fed mice and palmitate-treated hepatocytes in culture that Cyp D-mediated steatosis resulted from elevated mPT (mitochondrial swelling and cytosolic calcium), ROS generation, ER stress (IRE1α phosphorylation), p38 MAPK phosphorylation, and upregulation of sterol regulatory element-binding protein-1c (SREBP-1c) [58]. Elevated Cyp D, cytosolic calcium, and ER stress were also found to mediate hepatic steatosis originating from a deficiency of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), which is observed in NAFLD patients [60]. mPGDH regulated Cyp D levels by modulating Cyp D ubiquitination and proteasomal degradation.…”

Section: Cyclophilin Involvement In Mitochondrial Metabolismmentioning

confidence: 96%

“…Considerable evidence has accumulated that cyclophilin D (Cyp D) in the mitochondrial matrix participates directly or indirectly in many of these processes and that pharmacologically targeting Cyp D may improve the metabolic perturbations in NASH. Cyp D levels increase in animal models of obesity and metabolic syndrome and decrease when disease is reversed, for example by exercise [57][58][59][60][61]. The most understood mechanism by which Cyp D regulates mitochondrial function is its role as an inducer of the mitochondrial permeability transition (mPT) which is a common mechanism of cellular injury and death [62] ( Figure 1).…”

Section: Cyclophilin Involvement In Mitochondrial Metabolismmentioning

confidence: 99%

“…In vitro studies with CsA have reinforced findings from genetic knockout/knockdown by showing that cyclophilin inhibition can protect mitochondria from the kinds of metabolic disturbances that occur in NASH. For example, CsA blocked mPT in liver mitochondria following application of short-, medium-, and long-chain fatty acids or lysophosphatidylcholine [118][119][120][121]; blocked mPT and significantly reduced mitochondrial ROS, ATP depletion, and death of preadipocytes induced by high fatty acid concentrations [122]; blocked mPT and significantly reduced fructose-induced or high glucose-induced death of INS-1 pancreatic islet cells [123]; blocked mPT and restored the ATP deficit induced by long-chain fatty acids or palmitoyl-L-carnitine in cardiac mitochondria [124][125][126][127][128]; blocked mPT and prevented palmitate-induced insulin resistance in muscle mitochondria [107]; blocked hepatocyte death resulting from high glucose and hydrogen peroxide [129]; and alleviated fatty acid-induced ER stress gene induction, ROS elevation, and death of LO2 hepatocytes [60,130]. Düfer et al (2001), in contrast, found that CsA diminished glucose-induced insulin secretion of mouse pancreatic islets in vitro by inhibiting glucose-stimulated oscillations of the cytoplasmic free calcium concentration [131].…”

Section: Cyclophilin Involvement In Mitochondrial Metabolismmentioning

confidence: 99%

“…Intracellular signaling cascades producing these outcomes originate from three ER transmembrane sensors, inositol-requiring enzyme (IRE)-1α, protein kinase RNA-like ER kinase (PERK), and activating transcription factor (ATF)-6α [5,164,165]. ER stress was found to be a prominent mechanism in steatosis exacerbated by mGPDH knockout, and was facilitated by Cyp D, as demonstrated by complete reversal of the UPR response pathways by CsA [60]. In contrast, several studies show that CsA or specific cyclophilin isoform deletions (e.g.…”

Section: Cyclophilin Involvement In Cellular Injurymentioning

confidence: 99%

See 2 more Smart Citations

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

Ure¹,

Trepanier²,

Mayo³

et al. 2019

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism

Qu,

Liu,

Zhu

et al. 2023

Advanced Science

Self Cite

View full text Add to dashboard Cite

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte‐specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36‐mediated fatty acid uptake of podocytes via upregulating LXRα in an m6A‐dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.

show abstract

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Cited by 38 publications

References 49 publications

Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism

Contact Info

Product

Resources

About