TY - JOUR
T1 - SIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase
AU - Higgins, Cassandra B.
AU - Mayer, Allyson L.
AU - Zhang, Yiming
AU - Franczyk, Michael
AU - Ballentine, Samuel
AU - Yoshino, Jun
AU - DeBosch, Brian J.
N1 - Funding Information:
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through grants from the NHLBI (1R01HL147968), NIDDK (1R01DK126622), AASLD (Pilot Research Award), NCCIH (1R21AT010520-01), NIH/National Center for Advancing Translational Sciences (NCATS, #UL1TR002345), NIH R56 (DK115764), AGA-Gilead Sciences Research Scholar Award in Liver Disease, the AGA-Allergan Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease, the Washington University Digestive Disease Research Core Center (P30DK052574), Washington University Diabetes Research Center (P30DK020579), and the Robert Wood Johnson Foundation and the Longer Life Foundation. J.Y. is supported by NIDDK DK104995 and Nutrition & Obesity Research Center (P30DK056341). We thank Michael Wallendorf, PhD (Washington University Division of Biostatistics) for providing statistical consultations and review in preparing this paper.
Funding Information:
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through grants from the NHLBI (1R01HL147968), NIDDK (1R01DK126622), AASLD (Pilot Research Award), NCCIH (1R21AT010520-01), NIH/National Center for Advancing Translational Sciences (NCATS, #UL1TR002345), NIH R56 (DK115764), AGA-Gilead Sciences Research Scholar Award in Liver Disease, the AGA-Allergan Foundation Pilot Research Award in Non-Alcoholic Fatty Liver Disease, the Washington University Digestive Disease Research Core Center (P30DK052574), Washington University Diabetes Research Center (P30DK020579), and the Robert Wood Johnson Foundation and the Longer Life Foundation. J.Y. is supported by NIDDK DK104995 and Nutrition & Obesity Research Center (P30DK056341). We thank Michael Wallendorf, PhD (Washington University Division of Biostatistics) for providing statistical consultations and review in preparing this paper.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Calorie restriction abates aging and cardiometabolic disease by activating metabolic signaling pathways, including nicotinamide adenine dinucleotide (NAD+) biosynthesis and salvage. Nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting in NAD+ salvage, yet hepatocyte NAMPT actions during fasting and metabolic duress remain unclear. We demonstrate that hepatocyte NAMPT is upregulated in fasting mice, and in isolated hepatocytes subjected to nutrient withdrawal. Mice lacking hepatocyte NAMPT exhibit defective FGF21 activation and thermal regulation during fasting, and are sensitized to diet-induced glucose intolerance. Hepatocyte NAMPT overexpression induced FGF21 and adipose browning, improved glucose homeostasis, and attenuated dyslipidemia in obese mice. Hepatocyte SIRT1 deletion reversed hepatocyte NAMPT effects on dark-cycle thermogenesis, and hepatic FGF21 expression, but SIRT1 was dispensable for NAMPT insulin-sensitizing, anti-dyslipidemic, and light-cycle thermogenic effects. Hepatocyte NAMPT thus conveys key aspects of the fasting response, which selectively dissociate through hepatocyte SIRT1. Modulating hepatocyte NAD+ is thus a potential mechanism through which to attenuate fasting-responsive disease.
AB - Calorie restriction abates aging and cardiometabolic disease by activating metabolic signaling pathways, including nicotinamide adenine dinucleotide (NAD+) biosynthesis and salvage. Nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting in NAD+ salvage, yet hepatocyte NAMPT actions during fasting and metabolic duress remain unclear. We demonstrate that hepatocyte NAMPT is upregulated in fasting mice, and in isolated hepatocytes subjected to nutrient withdrawal. Mice lacking hepatocyte NAMPT exhibit defective FGF21 activation and thermal regulation during fasting, and are sensitized to diet-induced glucose intolerance. Hepatocyte NAMPT overexpression induced FGF21 and adipose browning, improved glucose homeostasis, and attenuated dyslipidemia in obese mice. Hepatocyte SIRT1 deletion reversed hepatocyte NAMPT effects on dark-cycle thermogenesis, and hepatic FGF21 expression, but SIRT1 was dispensable for NAMPT insulin-sensitizing, anti-dyslipidemic, and light-cycle thermogenic effects. Hepatocyte NAMPT thus conveys key aspects of the fasting response, which selectively dissociate through hepatocyte SIRT1. Modulating hepatocyte NAD+ is thus a potential mechanism through which to attenuate fasting-responsive disease.
UR - http://www.scopus.com/inward/record.url?scp=85125602053&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28717-7
DO - 10.1038/s41467-022-28717-7
M3 - Article
C2 - 35228549
AN - SCOPUS:85125602053
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1074
ER -