Journal
FEBS JOURNAL
Volume 288, Issue 12, Pages 3784-3798Publisher
WILEY
DOI: 10.1111/febs.15482
Keywords
caloric restriction; ChREBP; fibroblast growth factor 21; fructose; glucokinase; GLUT; intermittent fasting; ketogenic diet; mitochondrial pyruvate carrier; trehalose
Categories
Funding
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- NIH/NCCIH [1R21AT010520]
- AASLD Pilot Research Award
- NIH/NHLBI [1R01HL14796801A1]
- AGA-Allergan Pilot Research Award in NonAlcoholic Fatty Liver Disease
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The pervasion of three daily meals and snacks has coincided with a rise in obesity and cardiometabolic disorders. Research shows that calorie restriction and intermittent fasting have beneficial effects on cardiometabolic and other diseases, but sustainable adherence to strict lifestyle changes is rare.
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.
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