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.

Keywords: HDL-cholesterol; LDL-cholesterol; VLDL-cholesterol; carbohydrate restriction; lean mass hyper-responder; lipoprotein lipase; triglyceride-rich lipoproteins.

Figure 1

The Lipid Energy Model. (A) In the context of carbohydrate restriction, (1) glycogen depletion and (2) changes in circulating hormones stimulate hormone-sensitive lipase (HSL)-mediated secretion of non-esterified fatty acids (NEFA) by adipocytes to fuel oxidative tissues. (3) The liver captures circulating NEFAs and repackages them into triglycerides (TG), (4) secreted aboard VLDL. (5) Increased lipoprotein-lipase (LPL)-mediated VLDL turnover generates increased LDL-C and HDL-C. (Further details can be found in the main text.) The role of chylomicrons in the post-prandial state is presented later in the text. (B) The magnitude of carbohydrate restriction, adiposity, and energy expenditure each contribute, as independent variables, to the degree of LPL-mediated VLDL turnover and, thereby, to the magnitude of change of the triad components.

Figure 2

Lipoprotein lipase-mediated increase in LDL-C and HDL-C. In the presence of increased VLDL synthesis and secretion, lipoprotein lipase (LPL) activity liberates non-esterified fatty acids (NEFAs) for adipocytes and oxidative tissues. As TGs are lipolyzed, VLDLs shrink with loss of surface remnants (including cholesterol, phospholipids, and apolipoproteins) to HDL acceptor particles, and subsequent catabolism to LDL, resulting in increases in LDL particle mass, LDL-C, HDL particle mass and HDL-C.

Figure 3

High HDL is a result and cause of efficient lipoprotein lipase-mediated triglyceride-rich lipoprotein metabolism, and vice versa. (A) (1) Ingestion of dietary fat contributes to production of small nascent HDL particles and apoA-I-containing chylomicrons. (2) Lipoprotein lipase (LPL)-mediated catabolism of chylomicrons yields lipid-free/lipid-poor apoA-I to further contribute to the pool of small HDL “acceptor” particles. (3) As LPL-mediated catabolism of triglyceride-rich lipoproteins (TGRLs, including chylomicrons and VLDLs) occurs, TGRLs release surface remnants. Surface remnants, bilayer structures including cholesterol, phospholipids, and apolipoproteins, are predominantly taken up by small acceptor HDL particles. (4) Through this process, lipoproteins, originating as TGRLs, remodel to intermediate-density lipoprotein (IDL) and finally to LDL and smaller chylomicrons and are returned to the liver. Large cholesterol-rich HDL (produced largely as a function of efficient LPL-mediated TGRL turnover) returns cholesterol to the liver, (5) to be used in various ways, such as the synthesis of bile acids. (B) The contrapositive is that low plasma HDL concentrations can be a result and cause of inefficient LPL-mediated TGRL turnover, a phenomenon that can be used to mechanistically contrast atherogenic dyslipidemia and the Lean Mass Hyper-Responder (LMHR) phenotype and involves cholesteryl ester transfer protein (CETP). In atherogenic dyslipidemia, insufficient turnover yields elevated TGRLs, driving CETP-mediated transfer of TGs to HDL and LDL particles (by heterotypic and homotypic exchange, respectively). This increases hepatic lipase (HL)-mediated lipolysis with ensuing depletion of HDL and production of small dense LDL (sdLDL). Decreases in the HDL acceptor pool perpetuates the cycle. This is in contrast to the elevated LPL-mediated TGRL turnover proposed in LMHR, in which low TGRL leads to a low TG/CE ratio in lipoproteins and low CETP activity, resulting in cholesterol-rich HDL (and low levels of HL-mediated lipolysis) and elevated HDL-C and LDL-C.