The role of PPARalpha and growth hormone in hepatic lipid metaboism and atherosclerosis

Abstract

Dyslipidemia mainly results from oversecretion of apoB-containing lipoproteins from theliver and is one of the most important risk factors for the development of atherosclerosis.Growth hormone (GH) plays a key role in the regulation of lipoprotein metabolism and thus,disturbances in GH secretion are associated with dyslipidemia and cardiovascular disease.GH influences the activity of the nuclear hormone receptor peroxisome proliferator-activatedreceptor (PPAR)alpha, which regulates genes involved in lipid metabolism through interactionwith coactivators. PPARgamma coactivator-1 (PGC-1) has been shown to coactivate severaltranscription factors, including PPARalpha.GH transgenic mice on apoE-deficient background had larger atherosclerotic lesion area inthe thoracic aorta and more advanced lesions in aortic sinus compared to littermate controls.Changes in serum lipoproteins were most likely not involved in the accelerated lesionformation in GH transgenic mice since their lipoprotein profile was not worsened. Instead,higher blood pressure and an increased inflammatory response could contribute to thiseffect. Treatment of mice with a high dose of GH increased triglyceride secretion, serumapoB and cholesterol levels, whereas liver triglycerides were reduced. Most of the studiedeffects of GH were similar in PPARalpha-deficient and wild-type mice and thus independent ofPPARalpha. However, hepatic PPARgamma2 and Cyp4a10 mRNA expression were PPARalpha dependent,indicating that PPARalpha is important for the effect of GH on hepatic PPARgamma signaling and omega-oxidation. Treatment of mice and incubation of mouse hepatocytes with the PPARalpha agonistWy14,643 (Wy) resulted in hepatic triglyceride accumulation in parallel with increasedexpression of adipose differentiation-related protein (ADRP). Studies in mouse hepatocytesshowed that the increased triglyceride content was associated with inhibited triglyceridesecretion. ADRP overexpression also resulted in accumulation of triglycerides and decreasedtriglyceride secretion. The decreased secretion was not due to lack of triglycerides. Rather,PPARalpha activation prevents the availability of cytosolic triglycerides for VLDL assembly, inpart by increasing the expression of ADRP. Hepatic overexpression of PGC-1beta in miceinduced a hyperlipidemic response with a marked increase in apoB-containing lipoproteins.The hyperlipidemia was associated with increased diacylglycerol acyltransferase (DGAT)-1expression and plasma free fatty acids. The potentially beneficial effects of Wy on genescontrolling lipid metabolism were blunted by PGC-1beta overexpression.In summary, high GH levels are associated with increased atherosclerosis and hepatic VLDLsecretion. A few hepatic GH effects are dependent on PPARalpha. PPARalpha activation decreaseshepatic VLDL secretion by compartmentalization of intracellular triglycerides and hepaticPGC-1beta overexpression results in combined hyperlipidemia and decreased PPARalphasignaling.