This article reviews our understanding of effects of thyroid hormone excess and deficiency on hepatic metabolism of FFA, and consequent effects on production, secretion, and metabolism of plasma lipoproteins. In the hyperthyroid state the following alterations are observed. Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA). Esterification of fatty acid to triglyceride (TG) is reduced, as is the secretion of the very low density lipoprotein (VLDL) (including VLDL TG, cholesterol, and apoprotein); this may be due, in part, to decreased concentrations of glycerol-3-phosphate (G3P) in the hepatic cell. In the intact animal or patient, however, serum TG concentration is variable, which may reflect increased adipose tissue lipolysis and elevated concentrations of plasma FFA, which would tend to drive VLDL secretion by the liver. Clearance of the VLDL and its metabolic product, the low density lipoprotein (LDL), is increased, resulting in decreased plasma total and LDL cholesterol. Although high density lipoprotein (HDL) cholesterol may also be reduced, the ratio of LDL/HDL cholesterol is further decreased. The regulatory role of the lipoprotein apoproteins is less clear, but hepatic apolipoprotein (apo) B secretion (required for VLDL) is diminished, while apo-AI secretion (required for HDL) is stimulated, perhaps both reflecting rates of synthesis. Plasma concentrations of apo-AI are variable, dependent on relative rates of secretion and clearance. In the hypothyroid, many of these effects are reversed, which results in hyperlipoproteinemias and greater risk for the development of atherosclerotic cardiovascular disease.

Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after a JO-day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7 a-hydroxy-5, ll-diketotetranorprostane-1 ,16-dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet-rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.Free arachidonic acid is the precursor of the dienoic prostaglandins, including prostaglandins E2 and F 2a . In tissue and plasma, arachidonic acid is found in the ester linkage of phospholipids, cholesteryl esters, and triglycerides. Before arachidonic acid becomes available to prostaglandin synthetase, it must be released by either phospholipases or tri-

The lipids extracted from beef and pork muscle were fractionated into triglycerides, cephalins, and a mixture of lecithins and sphingomyelins. The fatty acid composition of these fractions was determined, and the possible effect of phospolipids on meat flavor was evaluated.Cold-water extracts of lean beef and lean pork contain desirable meat-flavor precursors. These extracts do not, however, contain any appreciable proportion of the lipids present in the lean meat. Lipids, particularly the phospholipids, are among the more unstable constituents of lean meat; and Younathan and Watts (1960) have recently suggested that the phospholipids play a major role in accelerating flavor deterioration in cooked meats. This paper is concerned with the effect on flavor of the lipids present in lean meat prior to preparation for consumption. Our studies have therefore been made on aged lean beef and lean pork. The meat tissue lipids have been separated into neutral lipids and phospholipids, the fatty acids present in these fractions determined, and the possible contribution of these fractions to either desirable or undesirable flavor evaluated. EXPERIMENTAL Extraction of lipids from muscle. As in previous flavor studies (Hornstein and Crowe, 1960; Hornstein et al., 196Ob), fresh meat 'was aged 10 days at 36-38°F. Several of the muscles were then dissected and stored at 0°F.As needed, samples of meat were thawed, fat was removed, and the trimmed muscle was cut into small sections. The extraction procedure was essentially that of Folch et al. (1957). One hundred grams of the diced meat were blended for 5 min with 900 ml of cold 2:l chloroform-methanol (all solvents are reagent grade and all solvent ratios are v/v) in an Oster blender (mention of trade names is for identification and implies no endorsement). The slurry was immediately filtered, then mixed with 0.2 its volume of water in a Z-L separatory funnel, and allowed to stand overnight at >S"C. The separation into two phases was clean-cut. The lower phase was drained and, without further washing, dried over anhydrous sodium sulfate, concentrated to a small volume on a rotary evaporator at room temperature under partial vacuum, quantitatively transferred with several ml of chloroform to a tared 125-ml Erlenmeyer flask, and dried on the rotary evaporator.Residual solvent was removed under high vacuum. The weighed residue was redissolved in 20 ml of 2O:l chloroform-methanol.Small amounts of undissolved material were removed by centrifugation. Separationof neutral fat from phospholipids by column chromatography.Fifty grams of silicic acid (Mallinckrodt AR loo-mesh) heated overnight at 130°C were slurried with chloroform and poured into a 2.5 X 90-cm column fitted with a sintered-glass disc. Air bubbles were removed by stirring the mixture with a long glass rod. The silicic acid was allowed to settle and the chloroform drained under slight nitrogen pressure. When the column was compact and with at least 15 cm of liquid above the interface, anhydrous sodium sulfate was added to f...

To study potential effects of hepatic cholesterol concentration on secretion of very-low-density lipoprotein (VLDL) by the liver, male rats were fed on unsupplemented chow, chow with lovastatin (0.1%), or chow with lovastatin (0.1%) and cholesterol (0.1%) for 1 week. Livers were isolated from these animals and perfused in vitro, with a medium containing [2-14C]acetate, bovine serum albumin and glucose in Krebs-Henseleit buffer, and with an oleate-albumin complex. With lovastatin feeding, the hepatic concentrations of cholesteryl esters and triacylglycerols before perfusion were decreased, although free cholesterol was unchanged. However, hepatic secretion of all the VLDL lipids was decreased dramatically by treatment with lovastatin. Although total secretion of VLDL triacylglycerol, phospholipid, cholesterol and cholesteryl esters was decreased, the decrease in triacylglycerol was greater than that in free cholesterol or cholesteryl esters, resulting in secretion of a VLDL particle enriched in sterols relative to triacylglycerol. In separate studies, the uptake of VLDL by livers from control animals or animals treated with lovastatin was measured. Uptake of VLDL was estimated by disappearance of VLDL labelled with [1-14C]oleate in the triacylglycerol moiety, and was observed to be similar in both groups. During perfusion, triacylglycerol accumulated to a greater extent in livers from lovastatin-fed rats than in control animals. The depressed output of VLDL triacylglycerols and the increase in triacylglycerol in the livers from lovastatin-treated animals was indicative of a limitation in the rate of VLDL secretion. Addition of cholesterol (either free cholesterol or human low-density lipoprotein) to the medium perfusing livers from lovastatin-fed rats, or addition of cholesterol to the diet of lovastatin-fed rats, increased the hepatic concentration of cholesteryl esters and the output of VLDL lipids. The concentration of cholesteryl esters in the liver was correlated with the secretion of VLDL by the liver. These data suggest that cholesterol is an obligate component of the VLDL required for its secretion. It is additionally suggested that cholesteryl esters are in rapid equilibrium with a small pool of free cholesterol which comprises a putative metabolic pool available and necessary for the formation and secretion of the VLDL. Furthermore, the specific radioactivity (d.p.m./mumol) of the secreted VLDL free cholesterol was much greater than that of hepatic free cholesterol, suggesting that the putative hepatic metabolic pool is only a minor fraction of total hepatic free cholesterol.