Milk was collected from mothers of 18 very premature (26 to 30 wk gestation age), 28 premature (31 to 36 wk), and six term (37 + wk) infants on day 2 to 3 (colostrum), and at 1, 3, 6, and 12 wk postpartum. Fat content for 154 milk samples was 2.80 g/dl gravimetrically and 2.66 g/dl by quantitative thin-layer chromatography. Fat content increased during lactation, whereas phospholipids and cholesterol declined. Concentrations of medium-chain fatty acids increased from colostrum to mature milk and were highest in preterm milk. Compensatory decreases were observed in very premature and premature oleic acid. Long-chain polyunsaturated fatty acids were highest in colostrum and reduced in mature milk. Long-chain polyunsaturated fatty acids were also higher in very premature and premature milk than in term milk. These elevated levels of readily absorbed medium-chain fatty acids and long-chain polyunsaturated fatty acids in preterm milk may be of special benefit for the needs of premature infants.

Peroxisome proliferator-activated receptor (PPAR)α and PPARγ agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARα/γ agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARα agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARγ agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P< 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels ( P < 0.01). We conclude that the PPARα/γ agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARγ ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARα activation, but without hepatomegaly.

(TG) requires the activation of fatty acids to long-chain acyl-CoAs (LC-CoA) by the enzyme acyl-CoA synthetase (ACSL). There are five known isoforms of ACSL (ACSL1, -3, -4, -5, -6), which vary in their tissue specificity and affinity for fatty acid substrates. To investigate the role of ACSL1 in the regulation of lipid metabolism, we used adenoviral-mediated gene transfer to overexpress ACSL1 in the human hepatoma cell-line HepG2 and in liver of rodents. Infection of HepG2 cells with the adenoviral construct AdACSL1 increased ACSL activity Ͼ10-fold compared with controls after 24 h. HepG2 cells overexpressing ACSL1 had a 40% higher triglyceride (TG) content (93 Ϯ 3 vs. 67 Ϯ 2 nmol/mg protein in controls, P Ͻ 0.05) after 24-h exposure to 1 mM oleate. Furthermore, ACSL1 overexpression produced a 60% increase in cellular LCA-CoA content (160 Ϯ 6 vs. 100 Ϯ 6 nmol/g protein in controls, P Ͻ 0.05) and increased [ 14 C]oleate incorporation into TG without significantly altering fatty acid oxidation. In mice, AdACSL1 administration increased ACSL1 mRNA and protein more than fivefold over controls at 4 days postinfection. ACSL1 overexpression caused a twofold increase in TG content in mouse liver (39 Ϯ 4 vs. 20 Ϯ 2 mol/g wet wt in controls, P Ͻ 0.05), and overexpression in rat liver increased [1-14 C]palmitate clearance into liver TG. These in vitro and in vivo results suggest a pivotal role for ACSL1 in regulating TG synthesis in liver.acyl-coenzyme A synthetase; hepatic triglyceride synthesis; adenovirus; fatty acid metabolism OBESITY AND ITS ASSOCIATED COMPLICATIONS of insulin resistance, cardiovascular disease, hypertension, hepatic steatosis, and type 2 diabetes have become a major health problem worldwide (50). All of these metabolic disorders exhibit altered regulation of lipid metabolism, which results in the intracellular accumulation of lipid in nonadipose tissues, but the intracellular mechanisms that control partitioning of fatty acids into different metabolic pathways are still being elucidated.Fatty acids can be metabolized in the pathways of ␤-oxidation, triglyceride synthesis, phospholipid synthesis, cholesterol ester synthesis, fatty acid elongation, and protein acylation and can also serve as signaling molecules (7,10,40). It is believed that the partitioning of intracellular fatty acids between storage pathways and ␤-oxidation is controlled by regulation of the mitochondrial acyl-CoA transporter carnitine palmitoyltransferase-1 (32), by regulation of metabolic gene expression (39), and by hormones including insulin. A number of recent studies suggest that partitioning might also involve the different isoforms of acyl-CoA synthetase (ACSL) (7,20,49).ACSL catalyzes the ATP-dependent acylation of fatty acids into long-chain acyl CoAs (LCA-CoAs) and is the first step in lipid metabolism after fatty acid entry into the cell. The LCA-CoAs can then enter the ␤-oxidation pathway for energy production or undergo further esterification for production of phospholipids, cholesterol esters, and triglycerides. Th...

SUMMARY The influence of homologous high density lipoprotein (HDL) and low density lipoprotein (LDL) and of whole hypercholesterolemic serum on the esterification of oleic acid and cholesterol was studied in rhesus monkey arterial smooth muscle cells. Whole hypercholesterolemic serum and isolated LDL stimulated cholesterol esterification as much as 10-fold using either cholesterol-1,2-3 H or oleate-l-14 C as substrate. At the same concentrations of cholesterol, HDL stimulated cholesterol esterification to a lesser extent, to a maximum of 3-fold. Associated with the stimulation of cholesterol esterification by LDL or whole hypercholesterolemic serum was a greater than 10-fold increase in the cholesteryl ester content of the arterial smooth muscle cells.Esterification to cholesterol reached a maximum after 8-12 hours of culture with either hypercholesterolemic serum or LDL. The stimulation of esterification was specific for esterification to cholesterol because there was little change in incorporation of fatty acid into triglycerides and phospholipids. These studies provide further evidence that a major consequence of the interaction of plasma LDL with the cellular elements of the arterial wall is a stimulation of cholesterol esterification. These studies, coupled with the observation that cholesteryl esters, more than any other single component, increase in the atherosclerotic artery, suggest an important role of a stimulation in cholesterol esterification in the pathogenesis of atherosclerosis.THERE NOW IS considerable information available describing the metabolic changes that occur in atherosclerotic arterial tissue.1 These include a number of alterations in the metabolism of proteins, carbohydrates, and lipids within the atherosclerotic artery. Although all of these metabolic changes contribute to the final expression of the disease, it is difficult to know which of them play a primary role in the initiation of the atherosclerotic lesion and which are results of the disease.The fact that cholesteryl esters accumulate within the atherosclerotic artery has been recognized for some time. 2As has been shown, an increase in arterial cholesteryl ester content is one of the first changes to occur in the arterial wall in experimentally produced atherosclerosis. This suggests that an alteration of cholesteryl ester metabolism may play a role in the initial events in the pathogenesis of atherosclerosis.3 Consistent with this hypothesis is the fact that a stimulation of cholesterol esterification can be demonstrated in arterial tissue prior to the appearance of grossly visible atherosclerotic lesions. Although cholesterol esterification appears to be one of the first metabolic parameters altered in the development of the atherosclerotic lesion, the actual mechanism of this stimulation is unclear. Considerable evidence suggests that it may result from the interaction of circulating plasma lipoproteins with the cellular elements of the arterial wall.3 "' To study the influence of a single component, such