CREBH-FGF21 axis improves hepatic steatosis by suppressing adipose tissue lipolysis.
Adipose tissue lipolysis produces glycerol and nonesterified fatty acids (NEFA) that serve as energy sources during nutrient scarcity. Adipose tissue lipolysis is tightly regulated and excessive lipolysis causes hepatic steatosis, as NEFA released from adipose tissue constitutes a major source of TG in the liver of patients with nonalcoholic fatty liver diseases. Here we show that the liver-enriched transcription factor CREBH is activated by TG accumulation and induces FGF21, which suppresses adipose tissue lipolysis, ameliorating hepatic steatosis. CREBH-deficient mice developed severe hepatic steatosis due to increased adipose tissue lipolysis, when fasted or fed a high-fat low-carbohydrate ketogenic diet. FGF21 production was impaired in CREBH-deficient mice, and adenoviral overexpression of FGF21 suppressed adipose tissue lipolysis and improved hepatic steatosis in these mice. Thus, our results uncover a negative feedback loop in which CREBH regulates NEFA flux from adipose tissue to the liver via FGF21.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA.
Jong-Gil
JG
Park
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA.
Xu
X
Xu
BCMB Allied Program, Weill Cornell Medical College, New York, USA.
Sungyun
S
Cho
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kyu Yeon
KY
Hur
Severance Biomedical Science Institute and Department of Internal Medicine; Yonsei University College of Medicine; Seoul, Korea.
Myung-Shik
MS
Lee
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands.
Sander
S
Kersten
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA.|BCMB Allied Program, Weill Cornell Medical College, New York, USA.
Ann-Hwee
AH
Lee
D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005234:Fatty Liver / Q000473:pathology*; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D008066:Lipolysis; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors