Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease.
Constitutive androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here we use leptin-deficient mice (ob/ob) and ob/ob, CAR(-/-) double mutant mice to identify a metabolic role of CAR in type 2 diabetes. Activation of CAR significantly reduces serum glucose levels and improves glucose tolerance and insulin sensitivity. Gene expression analyses and hyperinsulinemic euglycemic clamp results suggest that CAR activation ameliorates hyperglycemia by suppressing glucose production and stimulating glucose uptake and usage in the liver. In addition, CAR activation dramatically improves fatty liver by both inhibition of hepatic lipogenesis and induction of beta-oxidation. We conclude that CAR activation improves type 2 diabetes, and that these actions of CAR suggest therapeutic approaches to the disease.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Bingning
B
Dong
Pradip K
PK
Saha
Wendong
W
Huang
Wenling
W
Chen
Lutfi A
LA
Abu-Elheiga
Salih J
SJ
Wakil
Robert D
RD
Stevens
Olga
O
Ilkayeva
Christopher B
CB
Newgard
Lawrence
L
Chan
David D
DD
Moore
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D005234:Fatty Liver / Q000097:blood / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D007328:Insulin / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D010084:Oxidation-Reduction / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism
D001786:Blood Glucose; D000090702:Constitutive Androstane Receptor; D007328:Insulin; C000716328:Nr1i3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D015238:Sulfotransferases