Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice.
Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db/db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.
Xu
Aimin
A
Department of Medicine, Research Center of Heart, Brain, Hormone, and Healthy Aging, and Genome Research Center, University of Hong Kong, Hong Kong, China. amxu@hkucc.hku.hk
Lam
Michael C
MC
Chan
Kok Weng
KW
Wang
Yu
Y
Zhang
Jialiang
J
Hoo
Ruby L C
RL
Xu
Jian Yu
JY
Chen
Baoying
B
Chow
Wing-Sun
WS
Tso
Annette W K
AW
Lam
Karen S L
KS
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001798:Blood Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000139:chemically induced*; D005951:Glucose Tolerance Test; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001786:Blood Glucose; D001798:Blood Proteins