The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets

Abstract

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions.

Short-term hyper-caloric high-fat feeding on a ketogenic diet can lower low-density lipoprotein cholesterol: the cholesterol drop experiment

“…Framing these changes in the context of the LEM (review reference [4 ▪▪ ] for content), we here first focus on those induced by hypo-caloric feeding, the increase in LDL-C and TG. As a result of caloric restriction, there is a drop in insulin.…”

“…As a result of caloric restriction, there is a drop in insulin. This insulin drop would reduce hepatic LDL receptors to increase LDL-C and, for someone metabolically adapted to a carbohydrate restricted diet, would (along with an increase in ANGPTL4 activity [4 ▪▪ ,5]) reduce LPL activity at adipocytes, thereby reducing LPL-mediated VLDL-turnover, leading to increased TG. What's more, the decrease in LPL activity, while perhaps not dramatically changing HDL-C levels overall, would be expected to cause a shift towards a smaller lipid-poor HDL pool, which appears to have occurred in DF, as measured by Boston Heart HDL map in V2.…”

“…The Lipid Energy Model (LEM) provides a mechanistic explanation of these perhaps counterintuitive relationships [4 ▪▪ ]. Briefly, it postulates that the metabolic conditions created by carbohydrate restriction and subsequent hepatic glycogen depletion can, under the right circumstances, induce an increase in hepatic synthesis and export of TG-rich VLDL coupled with increased peripheral turnover and remodeling of these VLDL by lipoprotein lipase (LPL) in the periphery, generating the observed triad of high LDL-C and HDL-C with low TG (Supplemental Information: Lipid Energy Model , http://links.lww.com/COE/A34).…”

Low-carbohydrate diets in type 1 diabetes: balancing benefits and risks

“…This may be significant, considering PwT1Ds may be more likely to have a lean body mass compared with those with T2D. One hypothesis is that the shift towards fat as a main source of energy, increases hepatic cholesterol secretion, and this effect is blunted by insulin resistance [31 ▪ ]. There are genetic factors, which could also contribute to the increased LDL cholesterol.…”

Severe Dyslipidemia Mimicking Familial Hypercholesterolemia Induced by High-Fat, Low-Carbohydrate Diets: A Critical Review

“…It is thought that triglycerides are taken up very rapidly by peripheral tissues, which have come to rely heavily on fats as their metabolic substrate. The resulting lipid profile is characterized by markedly elevated levels of LDL-C and HDL-C, yet low triglycerides [ 58 ]. Our observation of elevated VLDL-C, LDL-C, and HDL-C, combined with relatively low levels of triglycerides found in patients 1 and 2, are in support of this ‘lipid energy model’.…”