PPARalpha activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes.
Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARalpha activation, adenovirus-mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRP-overexpressing cells was unchanged. In summary, PPARalpha activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.
Edvardsson
Ulrika
U
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden. ulrika.edvardsson@astrazeneca.com
Ljungberg
Anna
A
Lindén
Daniel
D
William-Olsson
Lena
L
Peilot-Sjögren
Helena
H
Ahnmark
Andrea
A
Oscarsson
Jan
J
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics; D042962:Acyl-CoA Oxidase / Q000235:genetics; D000818:Animals; D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism; D000070780:Perilipin-2; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014162:Transfection; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism*
D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D004041:Dietary Fats; D008565:Membrane Proteins; D047493:PPAR alpha; D000070780:Perilipin-2; D020025:Peroxisome Proliferators; C000602983:Plin2 protein, mouse; D011743:Pyrimidines; D014280:Triglycerides; D019308:Palmitic Acid; C006253:pirinixic acid; D042962:Acyl-CoA Oxidase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002334:Carnitine O-Palmitoyltransferase