The concept of carbohydrate-induced hypertriglyceridemia emerged as soon as the first studies comparing plasma lipid concentrations during high-fat and high-CHO diets were performed in the 1950s.9 24 Since high TG level appears as an independent risk factor for coronary heart disease (CHD),25 this possible adverse effect raised, in addition to the decrease in HDL cholesterol, concerns about using high-CHO diets for the prevention of atherosclerosis.13
These concerns are increased by the demonstration that the CHO-induced increase in TG occurs in the postprandial and postabsorptive states,7 26-28 and, despite initial evidence that the effect is only transient,29 persists on a long-term basis.16 The impact of increased CHO consumption on TG metabolism has been the subject of extensive research aimed at understanding the mechanisms responsible for the rise in TG concentrations and defining the factors modulating TG response to high-CHO diet.
An increase in postabsorptive TG concentrations may result from enhanced secretion of VLDL-TG, impaired clearance, or both phenomena (experimental evidence points to both). A defect in TG clearance was postulated as early as 1964 by Knittle and Ahrens.30 This possibility was supported by Mancini et al.31 who found via an intravenous fat tolerance test that feeding HCHO diets to normal subjects increased the half-life of plasma TG. Parks et al.32 found decreased clearance rates of VLDL-TG in normo- and moderately hypertriglyceridemic subjects fed HCHO
diets (68% CHO, mainly complex) for 5 weeks compared to a control diet (50% CHO). Conversely, Huff and Nestel33 found increased clearance rates after HCHO feeding; the type of CHO (simple or complex) was not stated and may play a role in the difference in responses. Blades and Garg34 found no modifications of TG clearance rate after a HCHO diet despite a large increase in TG concentrations. Their study was conducted in type II diabetic patients and the responses may differ in diabetic and control subjects.
The epuration of TG is dependent on the activity of lipoprotein lipase (LPL) that acts mainly on VLDL-TG and chylomicron TG and of hepatic lipase (HL) that acts on the remnants of VLDL and chylomicrons. Few data are available on the possible effects of HCHO diets on LPL and HL activities. Fredrickson et al.35 reported a decrease in postheparin plasma lipolytic activity after a HCHO diet but did not separate LPL and HL activities. Jackson et al. reported that HCHO diets lowered postheparin LPL activity; the effect was transient in men and persisted only in women.36 Campos et al. found a decreased plasma LPL activity after 6 weeks of HCHO diet in healthy men.37 Different results were obtained in type II diabetic patients: the HCHO diet induced no modification of HL activity28,34 and induced either an increase28 or no modification34 of postheparin LPL activity. This was not explained by lower values of lipase activities preceding the HCHO diet because the basal levels were similar to basal values obtained in control subjects. The divergent responses of control and diabetic subjects may play a role in their different TG clearance responses to HCHO diets.
LPL is located on the surfaces of capillary endothelial cells mainly in the heart, skeletal muscle, and adipose tissue. The regulation of its activity in muscles and adipose tissue appears different.38 Some data suggest that HCHO diets can lower skeletal muscle LPL activity,39,40 although no such decrease was found by Yost et al.41 However, a decrease in muscle skeletal muscle LPL activity may be compensated by an increase in adipose tissue LPL activity. Further studies should investigate the effect of HCHO diet on LPL activity, particularly the individual contributions of muscle and adipose tissue. Since LPL is activated by apoprotein CII and inhibited by apo-CIII, studies on the concentration of these apoproteins would also be useful. Huff and Nestel33 found that CHO feeding induced an increase in the concentration of apo-CIII in VLDL.
Raised TG levels may also result from increased VLDL secretion through an increase in the number of VLDL particles secreted, an increase in the amount of TG contained by each particle, or both phenomena. Since there is only one apo-B100 protein per VLDL particle, the number of circulating VLDL particles and their turnover rates can be appreciated, respectively, by measuring the concentration of apo-B100 and the incorporation of a labelled amino acid such as leucine into apo-B100 of VLDL.42 43 Measuring the turnover rate of the TG part of VLDL needs either the intravenous injection of VLDL previously labelled on the TG moiety or following the kinetics of the incorporation of intravenously injected glycerol or fatty acid in the TG part of VLDL.44 With the exception of Ginsberg et al. who found no modification of apo-B100 turnover rate,45 most studies using liquid formula or mainly simple carbohydrate to raise dietary CHO intake found an increase in apo-B100 or TG secretion rates.12,33,46-48 Studies of high-CHO diet with whole food and mainly complex CHOs revealed no modifications of TG or apo-B100 kinetics,3249 and showed major differences in metabolic effects induced by simple or complex CHOs.
Four potential sources for hepatic TG synthesis are available and could therefore contribute to the CHO-induced increase in VLDL-TG secretion: (1) fatty acids taken from the plasma pool of nonesterified fatty acids (NEFAs) that originate in the fasting state mainly from adipose tissue, (2) fatty acids provided by de novo hepatic lipo-genesis, (3) fatty acids provided by the degradation of TG-rich lipoproteins taken up by the liver, mainly remnants of chylomicrons and VLDL, and (4) fatty acids stored in the liver in TG droplets. Only the first two candidate sources have been investigated; the two others are awaiting appropriate methods.
Enhanced flow of plasma NEFA to the liver contributes to high TG levels in patients with endogenous, genetically controlled hypertriacylglycerolemia.50 No evidence points to such a mechanism during high CHO-induced hypertriglyceridemia. To our knowledge, the only reported comparison of plasma NEFA turnover rates in subjects receiving low- or high-CHO diets are by Schwarz et al.51 and Mittendorfer and Sidossis who found decreased whole body plasma NEFA flux after high-CHO diets and a trend of lower splanchnic NEFA uptake.51 Parks et al. found no modifications of the contribution of plasma NEFA reesterification to TG secretion rate in normo- or moderately hypertriglyceridemic subjects fed high-CHO diets.32 Mittendorfer and Sidossis52 showed that high-CHO diets decrease splanchnic fatty acid oxidation, suggesting that the percent of plasma fatty acids taken up by liver for hepatic reesterification was increased. Such a modification of liver fatty acid metabolism would be consistent with increased de novo hepatic lipogenesis. Indeed, a high-CHO diet could increase de novo lipogenesis through an increased flow of glucose through glycolysis and into the lipogenic hepatic acetyl-CoA pool through a stimulation of the expression of lipogenic genes.53 This has been examined since methods of measuring de novo liver lipogenesis in humans were developed.54-57 In normal subjects consuming moderately high fat diets, de novo lipogenesis contributes usually about 5% or less to the fatty acid pool of circulating TG445658 and represents a synthetic lipid rate of only 1 to 2 g/day. Increasing CHO intake can increase this contribution of de novo lipogenesis to about 30%,51 59 60 but this represents only few grams per day of lipid synthesized. The effect was observed during a large CHO overfeeding.
When the effects of raised CHO consumption are tested in an isoenergetic setting, a clear and large stimulation of de novo lipogenesis is observed only in subjects fed liquid formula rich in mono- or disaccharides.61-63 No stimulation3263 or only moderate stimulation (unpublished data) was observed in subjects fed high-CHO diets rich in complex CHOs. All these studies investigated mainly control subjects. It is important to know whether subjects at risk of developing hyperlipidemia, e.g., obese people, have increased hepatic lipogenesis and are more responsive to the effects of high-CHO diets.
Increased basal (in the postabsorptive state) hepatic lipogenesis was found in ad libitum-fed obese subjects58 64 and was directly related to BMI.58 This was also observed in obese subjects receiving isoenergetic diets for 3 days,65 but not when obese subjects received euenergetic diets for 2 weeks.61 This last observation and the normal decrease of hepatic lipogenesis in obese subjects during energy restriction64 suggest that there is no intrinsic, perhaps genetically determined, increased hepatic lipogenesis activity in obese patients. The acute response increase of liver lipogenesis to a high-CHO meal was more important in obese men than in lean men in a study by Marques-Lopes et al.65 This difference between lean and obese subjects during acute stimulation was not found during more prolonged overfeeding (96-h overfeeding with sucrose or glucose66 or 2 weeks of high-CHO diet).61 No clear evidence indicates enhanced sensitivity of hepatic lipogenesis to high-CHO intake in obese subjects.
In a study of Hudgins et al.,61 plasma TG levels were increased by a high-CHO diet and were directly correlated with hepatic lipogenesis. This suggests that the increased lipogenesis may play a role in the rise of TG concentration; however, the increased lipogenesis may be related simply to another metabolic process that plays a more important role such as diversion of the metabolism of plasma fatty acids taken up by the liver toward reesterification rather than oxidation.52
Lastly, the effect of high-CHO diets on adipose tissue lipogenesis should be investigated because a stimulating effect may on a long-term basis promote the development of excessive fat mass. Adipose tissue lipogenesis is usually considered less active than hepatic lipogenesis and therefore a minor metabolic pathway in humans.67,68 Recent studies suggest that human adipose tissue lipogenesis may become significant with a high-CHO diet.60,69 However, this was observed in subjects massively overfed with CHO. We found no evidence for such stimulation in subjects receiving moderately high CHO diets (unpublished data).
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