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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.

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