Loss of PDK4 switches the hepatic NF‐κB/TNF pathway from pro‐survival to pro‐apoptosis

Wu, Jiang; Zhao, Yulan; Park, Youngki; Lee, Ji-Young; Gao, Ling; Zhao, Jiajun; Wang, Li

doi:10.1002/hep.29902

Cited by 69 publications

(71 citation statements)

References 45 publications

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“…In the priming phase of PHx, the Kupffer cell–derived tumor necrosis factor (TNF) primes hepatocytes to re‐enter into the cell cycle . Pdk4 deficiency facilitates TNF expression . It will be interesting to determine the role of PDK4 in the priming phase after PHx as well as the hepatic activation of other signaling pathways during LR under Pdk4 ‐deficient conditions.…”

Section: Discussionmentioning

confidence: 99%

“…(11,33) Pdk4 deficiency facilitates TNF expression. (17) It will be interesting to determine the role of PDK4 in the priming phase after PHx as well as the hepatic activation of other signaling pathways during LR under Pdk4-deficient conditions.…”

Section: Discussionmentioning

confidence: 99%

“…(42) The function of PDK4 in LR needs to be further elucidated under pathological settings, such as in hepatotoxic models, given the irreconciliation that loss of PDK4 sensitizes mouse livers to apoptotic injury and that PDK4 activation may be essential for rapid LR in acetaminophen-induced liver injury. (4,17) Whether CD36 directly influences cell proliferation needs to be determined. FOXO1 suppresses endothelial CD36 transcription through nuclear association with histone deacetylase 7.…”

Section: Discussionmentioning

confidence: 99%

“…Wild-type (WT) and Pkd4 −/− knockout (KO) mice on a C57BL/6J (inbred strain) genetic background were described previously and handled in accordance with a protocol approved by the Institutional Animal Care and Use Committee at the University of Connecticut. (7,17,18) Mice were maintained on a 12-hour light/dark cycle with free access to water and standard chow before and after the surgery. Breeding mice were fed with irradiated sterile Teklad S-2335 mouse breeder diet (7904; Envigo Bioproducts, Inc., Madison, WI).…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

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PDK4‐Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice

et al. 2020

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Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two‐thirds partial hepatectomy (PHx). In Pdk4−/− PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4−/− mice developed more severe hypoglycemia. In Pdk4−/− PHx livers, the pro‐regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up‐regulation of CD36 contributed to the enhanced transient regeneration‐associated steatosis in Pdk4−/− PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate–activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4−/− livers. Moreover, we defined that PDK4‐regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Materials and Methods Animalsmentioning

confidence: 99%

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PDK4‐Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice

et al. 2020

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“…33 More importantly, a recent study demonstrated that genetic loss of PDK4 resulted in spontaneous cell death of human hepatocellular carcinoma cells (HCC), which was accompanied by mitochondrial dysfunction and increased production of ROS. 34 Moreover, PDK4-deficient mice suffered from increased chemically-induced liver injury, which could be prevented by inhibition of the NF- k B subunit p65. 34 These recent findings highlight the potential of PDK4 over-expression to alleviate chemically-induced liver injury and to reduce hepatic ROS levels, which is confirmed by the results outlined in our present study.…”

Section: Discussionmentioning

confidence: 99%

High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases

et al. 2019

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BACKGROUND: Patients with borderline resectable colorectal liver metastases (CRLM) frequently receive neoadjuvant chemotherapy (NC) to reduce tumour burden, thus making surgical resection feasible. Even though NC can induce severe liver injury, most studies investigating tissue-based prognostic markers focus on tumour tissue. Here, we assessed the prognostic significance of pyruvate-dehydrogenase-kinase isoenzyme 4 (PDK4) within liver tissue of patients undergoing surgical resection due to CRLM. METHODS: Transcript levels of hypoxia-adaptive genes (such as PDK isoenzymes) were assessed in the tissue of healthy liver, corresponding CRLM, healthy colon mucosa and corresponding tumour. Uni-and multivariate analyses were performed. Responses to chemotherapy upon up-or down-regulation of PDK4 were studied in vitro. RESULTS: PDK4 expression within healthy liver tissue was associated with increased overall survival and liver function following surgical resection of CRLM. This association was enhanced in patients with NC. PDK4 expression in CRLM tissue did not correlate with overall survival. Up-regulation of PDK4 increased the resistance of hepatocytes and colon cancer cells against chemotherapyinduced toxicity, whereas knockdown of PDK4 enhanced chemotherapy-associated cell damage. CONCLUSION: Our findings suggest that up-regulated PDK4 expression reduces hepatic chemotherapy-induced oxidative stress and is associated with improved postoperative liver function in patients undergoing multimodal treatment and resection of CRLM.

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3D Elastomeric Stent Functionalized with Antioxidative and Perivascular Tissue Regenerative Activities Ameliorated PVT Deprivation‐Induced Vein Graft Failure

Wang

Xiao

et al. 2023

Adv Healthcare Materials

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Clinically, arterial injuries are always accompanied with perivascular tissue damage, which may contribute to high failure rate of vein grafts due to intimal hyperplasia and acute thrombosis. In this study, a “perivascular tissue (PVT) deprivation” animal model is constructed to mimic clinical scenarios and identify the contribution of arterial PVT to the success of vein grafts. Proteomics analysis suggests that depriving PVT may exacerbate reactive oxygen species (ROS)‐induced endothelial apoptosis by up‐regulating inflammation response and oxidative stress. Locally administering metformin on vein grafts through 3D‐printed external stent (PGS‐PCL) shows antioxidative and anti‐inflammatory properties to protect cells from ROS invasion, thereafter decreasing acute thrombosis. Moreover, metformin induce rapid regeneration of perivascular adipose tissue in recipient regions, which improves patency by inhibiting intimal hyperplasia. Proteomics, western blot, and in vitro blocking tests reveal that metformin resists endothelial apoptosis through AMPK/mTOR and NFκB signaling pathways. To conclude, PVT deprivation exacerbates inflammatory response and oxidative stress in vein grafts bridging arterial circulation. Metformin‐loaded stent ameliorates “PVT damage” related vein graft failure, and enhances patency of through resisting endothelial apoptosis and regenerating arterial PVAT, offering a promising avenue to improve the success of vein grafts in clinic.

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Loss of PDK4 switches the hepatic NF‐κB/TNF pathway from pro‐survival to pro‐apoptosis

Abstract: PDK4 is indispensable to dictate the fate of TNF/NF-κB-mediated hepatocyte apoptosis. (Hepatology 2018).

Cited by 69 publications

References 45 publications

PDK4‐Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice

PDK4‐Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice

High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases

3D Elastomeric Stent Functionalized with Antioxidative and Perivascular Tissue Regenerative Activities Ameliorated PVT Deprivation‐Induced Vein Graft Failure

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