The pervasion of three daily meals and snacks is a relatively new introduction to our shared experience and is coincident with an epidemic rise in obesity and cardiometabolic disorders of overnutrition. The past two decades have yielded convincing evidence regarding the adaptive, protective effects of calorie restriction (CR) and intermittent fasting (IF) against cardiometabolic, neurodegenerative, proteostatic, and inflammatory diseases. Yet, durable adherence to intensive lifestyle changes is rarely attainable. New evidence now demonstrates that restricting carbohydrate entry into the hepatocyte by itself mimics several key signaling responses and physiological outcomes of IF and CR. This discovery raises the intriguing proposition that targeting hepatocyte carbohydrate transport to mimic fasting and caloric restriction can abate cardiometabolic and perhaps other fasting-treatable diseases. Here, we review the metabolic and signaling fates of a hepatocyte carbohydrate, identify evidence to target the key mediators within these pathways, and provide rationale and data to highlight carbohydrate transport as a broad, proximal intervention to block the deleterious sequelae of hepatic glucose and fructose metabolism.

Original languageEnglish
Pages (from-to)3784-3798
Number of pages15
JournalFEBS Journal
Issue number12
StatePublished - Jun 2021


  • ChREBP
  • GLUT
  • caloric restriction
  • fibroblast growth factor 21
  • fructose
  • glucokinase
  • intermittent fasting
  • ketogenic diet
  • mitochondrial pyruvate carrier
  • trehalose


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