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Human Performance Laboratory, Department of Kinesiology, University of Connecticut, U-1110, Storrs, CT 06269-1110
2To whom correspondence should be addressed. E-mail: jeff.volek{at}uconn.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • cholesterol • low-carbohydrate diet • ketogenic • triglycerides • lipoproteins
The aim of this review is to acquaint the reader with the resurgence of scientific papers published recently examining the effects of very low-carbohydrate diets (VLCDs)3 on blood lipoproteins and cardiovascular disease (CVD) risk factors. Despite the number of papers and the consistency of the results, most health practitioners including dietitians are unaware or misinformed on the topic and remain cautious about using VLCDs. VLCDs are discouraged by most professional organizations (1,2) because they contradict low-fat diets. This review will address whether it is reasonable to consider VLCDs as a dietary option with respect to outcomes related to CVD risk.
Despite government and medical disapproval of carbohydrate restriction, physicians personally use VLCDs at least as much as low-fat diets (3). Surveys indicate that millions of Americans are attempting to limit carbohydrate intake and the best-selling lay diet books have consistently focused on carbohydrate restriction. Interest in VLCDs among the scientific community has lagged behind the public. No formal definition of VLCDs exists, but arbitrary levels are defined as <50 g carbohydrate/d or <10% of total energy (4). Most VLCD studies do not control the amount of cholesterol, fiber, or quality of nutrients (e.g., type of fat). This is important because the effects could be enhanced further if, for example, a VLCD were combined with exercise or fiber-rich foods. Food choices compatible with this level of carbohydrate restriction (e.g., vegetables, beef, poultry, fish, oils, nuts/seeds, salads, cheese) generally result in an intake of 
60–65% fat and 20–25% protein. Nearly all VLCD studies are among free-living subjects; thus actual intakes are variable and dependent on subject preference and compliance. A major point is that VLCDs differ dramatically from current recommendations, and this fact has unnerved many people in the nutrition community.
Single-arm studies in normal-weight men and overweight/obese men and women evaluating the effects of VLCDs on blood lipids have ranged in duration from 1 to 12 mo (5–16). These studies show variable responses in total and LDL cholesterol (LDL-C) that are not explained by weight loss, suggesting a possible genetic explanation. There is a more consistent increase in HDL cholesterol (HDL-C) and decrease in triacylglycerol (TAG), although the magnitude of change is variable across studies. The greatest absolute and relative reductions in TAG occurred when a VLCD was combined with fish-oil supplementation (10,13) or in subjects with elevated TAG (>2.4 mmol/L) (14,16).
More recent prospective studies measured plasma lipid responses in subjects assigned to a VLCD or a low-fat diet (17–32). With 1 exception (22), experimental diets were hypoenergetic, involving overweight/obese men and women and ranging in duration from 1 to 12 mo. A common objective was to compare the effects of strict dietary carbohydrate restriction (i.e., Atkins diet) to a more conventional low-fat diet. Because of the free-living nature and lack of quality dietary education and follow-up, the degree of dietary compliance was poor in many studies, particularly as a function of time adhering to the diet intervention. Nevertheless, in all cases, the VLCD was still significantly lower in carbohydrate and higher in fat than the comparison low-fat diet and several studies did indeed achieve levels of carbohydrate < 50 g/d (17,19,22–24,28).
Although the magnitude of lipid responses varied, a notable degree of replication is evident across studies (Fig. 1). In all cases, the VLCD led to greater increases in total cholesterol, LDL-C, and HDL-C, and decreases in TAG. The mean difference between the relative changes in diets was greatest for TAG (22%) followed by HDL-C (11%), LDL-C (9%), and total cholesterol (7%). Although the low-fat diet was better at reducing total and LDL-C, the VLCD did not have a significant adverse effect on LDL-C in any study (defined as <7% increase) with the exception of a 15% increase in a carefully controlled study of normal-weight women who consumed isoenergetic (no change in body weight) VLCDs and low-fat diets in a crossover design (22). Interestingly, the increase in HDL-C with consumption of the VLCD was proportionally larger (+32%), thus lowering the total cholesterol/HDL-C ratio (22). The total cholesterol/HDL-C ratio tends to improve with weight loss; the decrease with consumption of a low-fat diet is driven by a reduction in LDL-C, whereas with consumption of a VLCD, it is due to an increase in HDL-C. The relative benefits of decreasing LDL over increasing HDL-C on mortality are debatable and are influenced by diet-induced modifications of other "emerging" CVD risk factors (i.e., fasting and postprandial TAG, LDL size distribution, LDL oxidation, and inflammatory markers).
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There is limited information on the effects of VLCDs on lipoprotein subfractions, oxidative LDL, and inflammatory markers. A predominance of smaller LDL particles has greater atherogenic potential (35). Using a nongradient PAGE procedure to separate LDL-C, we showed repeatedly that a VLCD shifts the particle distribution to a larger size, resulting in significant increases in peak and mean LDL diameter and decreases in the proportion of small, dense LDL particles (11,22,24). This effect is most evident in men and women who start with a predominance of smaller LDL particles (i.e., pattern B). Other studies in patients with CVD and a high prevalence of metabolic syndrome showed similar results using gradient gel electrophoresis (29) and NMR spectroscopy (15,30). A VLCD also increases the distribution of larger HDL particles (15,30), which is believed to be the cardioprotective fraction (36).
Based on the lipoprotein findings presented in the above-mentioned studies, we propose a model to explain the modifications in lipoprotein metabolism on a VLCD (Fig. 3). Repeated ingestion of a VLCD initially increases circulating TAG-rich chylomicrons, which are cleared rapidly by lipoprotein lipase (LPL) bound to the luminal surface of capillary endothelial cells in skeletal muscle and adipose tissue. Although speculative, we suggest that a VLCD increases muscle LPL, enhancing TAG clearance. A VLCD leads to lower glucose and insulin levels, which decrease LPL and increase hormone-sensitive lipase (HSL), promoting TAG hydrolysis and increasing fatty acid (FA) rate of appearance. LPL-mediated lipolysis of chylomicrons results in release of FA that is either taken up by the underlying tissue or escapes into the circulation. Any increase in FA delivery to skeletal muscle is balanced by an increase in fat oxidation as evident from the postabsorptive respiratory exchange ratios near 0.7. Circulating FAs are taken up by the liver and preferentially diverted away from esterification to TAG and toward mitochondrial oxidation to acetyl CoA. Accumulation of acetyl CoA exceeding the capacity for mitochondrial oxidation results in the formation of ketones. Reduced hepatic production of TAG results in less VLDL synthesis and secretion into the circulation. LPL-mediated lipolysis of VLDL results in transfer of unesterified cholesterol, phospholipid (PL), apolipoprotein (apo)E, apoC-II, and apoC-III to form mature HDL-C. The remaining remnant particles are either taken up by the liver or converted to LDL. Decreased circulating VLDL, particularly in the postprandial period, results in less cholesterol ester transfer protein (CETP)-mediated neutral lipid exchange with LDL-C. A reduction in hepatic lipase (HL) prevents larger LDL-C from being delipidated to smaller, dense (atherogenic) LDL, resulting in a predominance of larger LDL particles.
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(hsTNF-), interleukin-6 (hsIL-6), CRP, and soluble intracellular adhesion molecule-1 (sICAM-1) after consumption of a hypoenergetic VLCD (–45, –51, –55, and –18%, respectively) did not differ from the low-fat diet (–42, –46, –48, and –20%, respectively) (37). In normal-weight women who consumed an isoenergetic VLCD diet, there were no changes in CRP, IL-6, and TNF- (22). In a 6-mo weight loss study, CRP levels decreased to a similar extent with consumption of a VLCD (13%) and low-fat diet (7%), but subjects with CRP >30 mg/L at baseline demonstrated a significantly greater decrease with consumption of the VLCD independently of weight loss (30). These data indicate that weight loss is the driving force underlying the reduction in inflammatory markers and not the composition of the diet. A VLCD may be more effective at lowering CRP in high-risk individuals, but this must be confirmed in additional studies. In conclusion, VLCDs consistently improve postabsorptive and postprandial TAG, HDL-C, and the distribution of LDL-C subclasses (i.e., the dyslipidemia of metabolic syndrome). There is an urgent need for innovative measures to address metabolic syndrome as a growing medical, societal, and economic problem. A primary problem with low-fat/high-carbohydrate diets is that they contribute to carbohydrate-induced hypertriglyceridemia (38), a major problem underlying the metabolic syndrome, challenging the appropriateness of current diet recommendations (39,40). Promotion of a single diet is not justified, given the known variability in response to the same diet. Considering the favorable and consistent outcomes in many carbohydrate-restricted diet studies, we encourage a more unbiased and dispassionate discussion of the relative merits of VLCD by the nutrition and medical communities.
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; CETP, cholesterol ester transfer protein; CVD, cardiovascular disease; FA, fatty acid; HDL-C, HDL cholesterol; HL, hepatic lipase; hsCRP, high-sensitivity C-reactive protein; hsIL-6, high-sensitivity interleukin-6; hsTNF-, high-sensitivity tumor necrosis factor-; HSL, hormone-sensitive lipase; LDL-C, LDL cholesterol; LPL, lipoprotein lipase; PL, phospholipids; sICAM-1, soluble intracellular adhesion molecule-1; TAG, triacylglycerol; VLCD, very low-carbohydrate diet.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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