Journal Article

Vitamin B2 enables regulation of fasting glucose availability

Lorenzi, Philip L, Kaipparettu, Benny Abraham, Wang, Liping, Sharp, Robert, Moore, David D, Kim, Kang Ho, Park, Jun Hyoung, Nuotio-Antar, Alli M, Tan, Lin, Putluri, Vasanta, Putluri, Nagireddy, Li, Xin, Summers, Scott A, Saha, Pradip, Cox, Aaron R, Masschelin, Peter M, Ochsner, Scott A, Sun, Zheng, Hartig, Sean M, Felix, Jessica B, McKenna, Neil J

2023

Overview

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Amino acids / Animals / Body composition / Body fat / Body weight / Cell Biology / Chemical reduction / Dextrose / Diet / Disease / Energy / FAD / Fasting / Fasting - metabolism / Fatty Acids - metabolism / Fatty liver / Fenofibrate / Flavin / Flavin-adenine dinucleotide / Flavin-Adenine Dinucleotide - metabolism / Flavoproteins / Flavoproteins - metabolism / Food / Gene expression / Gluconeogenesis / Glucose / Glucose - metabolism / Homeostasis / Hypoglycemia / Inborn errors of metabolism / Instrument industry / Intolerance / Lipodystrophy / Liver / Liver - metabolism / Liver diseases / Metabolic response / Metabolism / Mice / Morphology / Non-alcoholic Fatty Liver Disease - metabolism / nuclear receptor / Nutrient deficiency / Oxidation / Oxidation-Reduction / Phenotypes / Physiological aspects / PPAR alpha - genetics / PPAR alpha - metabolism / Statistical analysis / Steatosis / Transcription activation / Vitamin B / Vitamin deficiency / Vitamins