PPARα activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes

Abstract

Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferatoractivated receptor a (PPARa) 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 PPARa activation, adenovirusmediated 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 ADRPoverexpressing cells was unchanged. In summary, PPARa activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP. Peroxisome proliferator-activated receptor a (PPARa) is a ligand-activated transcription factor that plays a key role in the regulation of genes involved in carbohydrate, lipid, and lipoprotein metabolism (for review, see 1).PPARa is highly expressed in tissues with high mitochondrial and peroxisomal b-oxidation activities, such as liver, heart, kidney, and skeletal muscle (2-5). In humans, treatment with PPARa agonists (i.e., fibrates) results in decreased plasma levels of triglycerides and increased plasma HDL cholesterol levels (6, 7). The triglyceride-lowering effect of fibrates is partly explained by increased lipoprotein lipase expression (8) and downregulation of hepatic apolipoprotein C-III expression (9, 10), which results in increased turnover of VLDL. In addition, fibrates have been shown to decrease the plasma concentration of atherogenic small dense LDL particles (11, 12), indicating decreased hepatic triglyceride secretion, because small dense LDLs are products of triglyceride-rich VLDL (VLDL 1 ) particles (13). Indeed, fibrates have been shown to decrease VLDL triglyceride secretion in both humans and rats (14,15). In primary rat hepatocytes, fibrates reduced triglyceride secretion and decreased the size of the secreted apolipoprotein B (apoB)-containing lipoproteins (16). The reduced triglyceride secretion may be explained by decreased triglyceride biosynthesis in rat hepatocytes (16,17). However, in vivo in rats, incorporation of palmitate into liver triglyc...

PPARα activators and fasting induce the expression of adipose differentiation-related protein in liver

“…PPARa-mediated transcriptional regulation of ADFP in liver was recently also demonstrated by others (50), which supports our findings.…”

mRNA LEVELS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AND THEIR COACTIVATORS ARE AFFECTED BY GLUCOSE DEPRIVATION AND OLEATE IN HUMAN HEPATOMA HepG2 CELLS

“…In comparison, in the above mentioned study, Fujiwara et al (2003) detected stimulation of PPAR-γ mRNA expression (isoform not specifi ed) in HepG2 cells following 24 h oleate treatment 27 . In a recent study by Edvardsson et al (2006) isolated mouse hepatocytes maintained with 0.5 mmol/l oleate (in the presence of 0.75% albumin and 11 mmol/l glucose) were markedly upregulated PPAR-γ2 mRNA amount, whereas that of PPAR-γ1 mRNA remained unchanged 30 . Species and model variations are likely to be taken into account to un-243 mRNA levels of peroxisome proliferator-activated receptors and their coactivators are aff ected by glucose deprivation and oleate in human hepatoma HepG2 cells derstand the cause of these discrepancies.…”

Glucagon regulates intracellular distribution of adipose differentiation-related protein during triacylglycerol accumulation in the liver

“…It is well known that the addition of fatty acid to various cells induces ADRP expression and LD formation and that PPAR-RXR heterodimers are involved in mRNA expression of the ADRP gene (19)(20)(21)(22)(23)(24)(25). We tested the effect of fatty acids on the distribution of ADRP using HuH-7 hepatocytes, but we did not observe ADRP distribution in the iLD fractions by…”

“…The expression of Adrp mRNA is induced not only in adipocytes but also in many other types of cells upon lipid accumulation (17)(18)(19)(20)(21). It is reported that peroxisome-proliferator activated protein (PPAR)-retinoid X receptor (RXR) heterodimers are responsible for ADRP transcription, while PPAR ␥ is the major subtype in adipose tissue and the placenta ( 22,23 ), PPAR ␦ is crucial in macrophages ( 19 ), and PPAR ␣ acts in the liver ( 20,24 ).…”