Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor.
We reported previously that angiopoietin-like protein3 (ANGPTL3), a liver-specific secretory factor, increased plasma triglyceride (TG) via inhibition of lipoprotein lipase and free fatty acid (FFA) by activating adipose-lipolysis. The current study examined the regulation of Angptl3 by leptin and insulin, both of which are key players in the metabolic syndrome. Angptl3 expression and plasma ANGPTL3 levels were increased in leptin-resistant C57BL/6J(db/db) and -deficient C57BL/6J(ob/ob) mice, relative to the control. Leptin supplements decreased Angptl3 gene expression and plasma ANGPTL3 in C57BL/6J(ob/ob) mice. The changes of Angptl3 were associated with alterations of plasma TG and FFA levels. Leptin treatment directly suppressed Angptl3 gene expression in hepatocytes. Angptl3 gene expression and plasma protein levels were also increased in insulin-deficient streptozotocin-treated mice. Insulin treatment of hepatocytes decreased Angptl3 gene expression and protein secretion. Our results suggest that elevated ANGPTL3 by leptin- or insulin-resistance is attributed to increased plasma TG and FFA concentrations in obesity.
Shimamura
Mitsuru
M
Biomedical Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Matsuda
Morihiro
M
Ando
Yosuke
Y
Koishi
Ryuta
R
Yasumo
Hiroaki
H
Furukawa
Hidehiko
H
Shimomura
Iichiro
I
D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified / Q000097:blood; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013311:Streptozocin / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood*
D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D011994:Recombinant Proteins; D014280:Triglycerides; D013311:Streptozocin