Pigment epithelium-derived factor (PEDF) suppresses IL-1β-mediated c-Jun N-terminal kinase (JNK) activation to improve hepatocyte insulin signaling.
Pigment epithelium-derived factor (PEDF) is an antiinflammatory protein that circulates at high levels in the metabolic syndrome. Metabolic studies of PEDF knockout (KO) mice were conducted to investigate the relationship between PEDF, inflammatory markers, and metabolic homeostasis. Male PEDF KO mice demonstrated a phenotype consisting of increased adiposity, glucose intolerance, and elevated serum levels of metabolites associated with the metabolic syndrome. Genome expression analysis revealed an increase in IL-1β signaling in the livers of PEDF KO mice that was accompanied by impaired IRS and Akt signaling. In human hepatocytes, PEDF blocked the effects of an IL-1β challenge by suppressing activation of the inflammatory mediator c-Jun N-terminal kinase while restoring Akt signaling. RNA interference of PEDF in human hepatocytes was permissive for c-Jun N-terminal kinase activation and decreased Akt signaling. A metabolomics profile identified elevated circulating levels of tricarboxyclic acid cycle intermediates including succinate, an inducer of IL-1β, in PEDF KO mice. Succinate-dependent IL-1β expression was blocked by PEDF in PEDF KO, but not wild-type hepatocytes. In vivo, PEDF restoration reduced hyperglycemia and improved hepatic insulin signaling in PEDF KO mice. These findings identify elevated PEDF as a homeostatic mechanism in the human metabolic syndrome.
Sections of Digestive Diseases (A.K.G., Y.I., P.P., C.C.); Endocrinology, Department of Medicine (A.L.B., V.T.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Veterans Affairs Connecticut Healthcare System (P.P., V.T.S., C.C.), West Haven, Connecticut 06516; Department of Biomedical Engineering (S.J., M.S.), Yale University, New Haven, Connecticut 06511; Department of Pathology (S.E.C.), St Louis University School of Medicine, St Louis, Missouri 63104; and Department of Biomedical Sciences (J.D.), University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201.
Arijeet K
AK
Gattu
Andreas L
AL
Birkenfeld
Yasuko
Y
Iwakiri
Steven
S
Jay
Mark
M
Saltzman
Jennifer
J
Doll
Petr
P
Protiva
Varman T
VT
Samuel
Susan E
SE
Crawford
Chuhan
C
Chung
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D005136:Eye Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008863:Microspheres; D009414:Nerve Growth Factors / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D019308:Palmitic Acid / Q000737:chemistry; D010641:Phenotype; D034622:RNA Interference; D015843:Serpins / Q000378:metabolism*; D015398:Signal Transduction; D019802:Succinic Acid / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D007328:Insulin; D053583:Interleukin-1beta; D048031:JNK Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors; D019308:Palmitic Acid; D015843:Serpins; D019802:Succinic Acid; D000099174:Pigment Epithelium-Derived Factor