PTEN Down‐Regulation Promotes β‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice

Kachaylo, Ekaterina; Tschuor, Christoph; Calo, Nicolas; Borgeaud, Nathalie; Ungethüm, U.; Limani, Përparim; Piguet, Anne‐Christine; Dufour, Jean–François; Foti, Michelangelo; Graf, Rolf; Clavien, Pierre Alain; Humar, Bostjan

doi:10.1002/hep.29226

Cited by 48 publications

(59 citation statements)

References 42 publications

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“…B,F). A recent study showed that PTEN coordinates liver growth with its energy demands and emphasizes the requisition of lipids for LR . We identify PDK4 as a key molecule coordinating hepatic lipid homeostasis with liver growth, but the role of PDK4 in the metabolism of extrahepatic tissues during LR needs to be identified.…”

Section: Discussionmentioning

confidence: 87%

“…). The TRAS is essential to LR, and FA uptake is an important element for TG storage . Hepatic FA metabolism is a tightly controlled process that is subjected to regulation at levels of uptake, oxidation, de novo synthesis, intracellular transport, and export to circulation.…”

Section: Resultsmentioning

confidence: 99%

“…Mild steatosis and TRAS are beneficial to LR; however, severe and chronic lipid overload may cause successive inflammation and impair LR . De novo hepatic lipogenesis is not required for the development of TRAS, and β‐oxidation of FAs serves as the predominant source of new ATP production in the regenerative liver . Indeed, β‐oxidation rather than lipogenesis increases in Pdk4 −/− ‐PHx livers (Fig.…”

Section: Discussionmentioning

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: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Nonetheless, 1‐week survival (ie, the best measure for a functional liver recovery) appeared to be slightly compromised ( P = 0.09) after Yap1 knockdown and hepatectomy (Figure C), suggesting that the early promotion of liver weight gain (ie, up to 32 hours) through YAP1 is vital to regeneration after tissue loss. Finally, the macroscopic appearance of α Yap1 ‐siRNA‐treated liver was pale at 48 hours after sHx (Figure C), pointing to persisting steatosis that typifies liver remnants with a regenerative deficiency …”

Section: Resultsmentioning

confidence: 99%

“…To get better insight into the physiological role of YAP1 during liver regeneration, we examined its expression after extended hepatectomy (eHx). Liver failure after eHx develops due to deficient progression through the hepatocellular S‐ and M‐phases associated with a shutdown of pro‐proliferative pathways . If YAP1 indeed functions in the early cell cycle (including the S‐phase) but is dispensable for the M‐phase, its activity should be impaired at 32 hours, but not 48 hours, after eHx.…”

Section: Resultsmentioning

confidence: 99%

Yes-associated protein promotes early hepatocyte cell cycle progression in regenerating liver after tissue loss

et al. 2018

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The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo‐YAP1 pathway, a key controller of organ size. Yes‐associated protein 1 (YAP1)—a growth effector usually restrained by Hippo signaling—is believed to be of particular importance; however, its role in liver regeneration remains ill‐defined. To explore its function, we knocked down YAP1 prior to standard 70%‐hepatectomy (sHx) using a hepatocyte‐specific nanoformulation. Knockdown was effective during the major parenchymal growth phase (S‐phase/M‐phase peaks at 32 hours/48 hours post‐sHx). Liver weight gain was completely suppressed by the knockdown at 32 hours, but was reaccelerated toward 48 hours. Likewise, proliferative markers, Ccna2/b2 and YAP1 target gene expression were downregulated at 32 hours, but re‐elevated at 48 hours post‐sHx. Nonetheless, knockdown slightly compromised survival after sHx. When assessing a model of resection‐induced liver failure (extended 86%‐hepatectomy, eHx) featuring deficient S‐ and M‐phase progression, YAP1 was not induced at 32 hours, but upregulated at 48 hours post‐eHx, confirming its dissociation from M‐phase regulation. Therefore, YAP1 is vital to push hepatocytes into cycle and through the S‐phase, but is not required for further cell cycle progression during liver regeneration. The examination of YAP1 in human livers suggested its function is conserved in the regenerating mammalian liver.

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PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

Wen

Jiao

et al. 2022

Clinical & Translational Med

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Background & aims Transient regeneration–associated steatosis (TRAS) is a process of temporary hepatic lipid accumulation and is essential for liver regeneration by providing energy generated from fatty acid β‐oxidation, but the regulatory mechanism underlying TRAS remains unknown. Parkinsonism‐associated deglycase (Park7)/Dj1 is an important regulator involved in various liver diseases. In nonalcoholic fatty liver diseased mice, induced by a high‐fat diet, Park7 deficiency improves hepatic steatosis, but its role in liver regeneration remains unknown Methods Park7 knockout (Park7−/−), hepatocyte‐specific Park7 knockout (Park7△hep) and hepatocyte‐specific Park7‐Pten double knockout mice were subjected to 2/3 partial hepatectomy (PHx) Results Increased PARK7 expression was observed in the regenerating liver of mice at 36 and 48 h after PHx. Park7−/− and Park7△hep mice showed delayed liver regeneration and enhanced TRAS after PHx. PPARa, a key regulator of β‐oxidation, and carnitine palmitoyltransferase 1a (CPT1a), a rate‐limiting enzyme of β‐oxidation, had substantially decreased expression in the regenerating liver of Park7△hep mice. Increased phosphatase and tensin homolog (PTEN) expression was observed in the liver of Park7△hep mice, which might contribute to delayed liver regeneration in these mice because genomic depletion or pharmacological inhibition of PTEN restored the delayed liver regeneration by reversing the downregulation of PPARa and CPT1a and in turn accelerating the utilization of TRAS in the regenerating liver of Park7△hep mice Conclusion Park7/Dj1 is a novel regulator of PTEN‐dependent fatty acid β‐oxidation, and increasing Park7 expression might be a promising strategy to promote liver regeneration.

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PTEN Down‐Regulation Promotes β‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice

Cited by 48 publications

References 42 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

Yes-associated protein promotes early hepatocyte cell cycle progression in regenerating liver after tissue loss

PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

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