Dietary fat and carbohydrate affect the metabolism of protein-based high-density lipoprotein subspecies

Abstract

Purpose of review: Dietary fat compared to carbohydrate increases the plasma concentration of high-density lipoprotein (HDL)-cholesterol. However, neither the mechanism nor its connection to cardiovascular disease is known.

Recent findings: Protein-based subspecies of HDL, especially those containing apolipoprotein E (apoE) or apolipoprotein C3 (apoC3), offer a glimpse of a vast metabolic system related to atherogenicity, coronary heart disease (CHD) and other diseases. ApoE stimulates several processes that define reverse cholesterol transport through HDL, specifically secretion of active HDL subspecies, cholesterol efflux to HDL from macrophages involved in atherogenesis, size enlargement of HDL with cholesterol ester, and rapid clearance from the circulation. Dietary unsaturated fat stimulates the flux of HDL that contains apoE through these protective pathways. Effective reverse cholesterol transport may lessen atherogenesis and prevent disease. In contrast, apoC3 abrogates the benefit of apoE on reverse cholesterol transport, which may account for the association of HDL that contains apoC3 with dyslipidemia, obesity and CHD.

Summary: Dietary unsaturated fat and carbohydrate affect the metabolism of protein-defined HDL subspecies containing apoE or apoC3 accelerating or retarding reverse cholesterol transport, thus demonstrating new mechanisms that may link diet to HDL and to CHD.

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FIGURE 1

Effects of dietary fat and carbohydrate on plasma cholesterol levels. LDL, low-density lipoprotein.

FIGURE 2

HDL metabolism across the HDL sizes: new model. HDL from small to large size: preβ, α3, α2, α1. Figure summarizing data from Mendivil et al. Arterioscler Thromb Vasc Biol. 2016. HDL, high-density lipoprotein.

FIGURE 3

Distribution and disease risk of HDL subspecies containing apoE and/or apoC3. (a) Plasma apoA1 distribution across HDL subspecies that contain apoE and apoC3 (E+C3+), apoE but not apoC3 (E+C3−), apoC3 but not apoE (E-C3+), and neither apoE or apoC3 (E-C3−) in normal and obese people. (b) Percentage apoA1 distribution in each HDL subspecies from large (α1) to small (preβ) HDL sizes. (a,b) Figure summarizing data from Talayero et al. J Lipid Res. 2014. (c) Association of apoE and/or apoC3 containing HDL subspecies with CHD. Figure summarizing data from Morton, Koch et al. JCI Insight. 2018. apoC3, apolipoprotein C3; apoE, apolipoprotein E; CHD, coronary heart disease; HDL, high-density lipoprotein.

FIGURE 4

Effects of dietary unsaturated fat and carbohydrate on the metabolism of apoA1 in HDL that contains apoE (a), and of the apoE protein on HDL (b). Unsaturated fat, when replacing carbohydrate, increases apoA1 flux from the liver to medium α3 particles containing apoE and from α3 to preβ (solid blue arrows from the liver to α3 and from α3 to preβ). ApoE also increases the catabolic rate of large α1 and α2 particles (arrows out of α1 and α2) and tends to increase the size expansion of small preβ HDL to larger α1 and α2 (dashed blue arrows from prebeta to α1 and α2). On the other hand, unsaturated fat, when replacing carbohydrate, decreases the flux of apoE protein itself from the liver to α2 and α3 (red arrows from liver into α2 and into α3) and decreases the catabolic rate of apoE on α1 and α3 HDL (red arrows out of α1 and out of α3). Figure summarizing data from Morton et al. JCI Insight. 2019 (a) and Andraski et al. Arterioscler Thromb Vasc Biol. 2019 (b). HDL, high-density lipoprotein.

FIGURE 5

Effects of apoC3 on the metabolism of apoA1 on apoE-containing HDL (Panel a) and the effect of diet on apoC3 on HDL (Panel b). (a) ApoC3 on HDL that contains apoE mitigates the beneficial metabolic effects of apoE. ApoC3 decreases apoA1 clearance rates, decreases size expansion, and increases the risk of coronary heart disease (CHD). Data summarized from Morton, Koch. JCI Insight. 2018. (b) Dietary unsaturated fat, when replacing carbohydrate, decreases apoC3 synthesis but does not alter its clearance rate. Figure summarizing data from Andraski et al. Arterioscler Thromb Vasc Biol. 2019. apoC3, apolipoprotein C3; apoE, apolipoprotein E; CHD, coronary heart disease; HDL, high-density lipoprotein.

FIGURE 6

Effects of dietary unsaturated fat and carbohydrate on the HDL proteome and the tracer enrichment curves of several HDL proteins. (a) Average (n = 12 participants) percentage distribution of 12 HDL proteins across 5 HDL sizes on a high unsaturated fat and a high carbohydrate diet. Each protein has a distinct distribution across HDL size, and diet does not alter this distribution. (b) Representative enrichment curves from the 12 HDL proteins that have been monitored by parallel reaction monitoring mass spectrometry. Eight of these proteins (top panel) were analyzed on a high fat and high carbohydrate diet. The effect of diet on the remaining 4 proteins (bottom panel) was not studied. Enrichment curves are shown for the size fraction in which each protein is most abundant. Figure summarizing data from Andraski et al. Arterioscler Thromb Vasc Biol. 2019 (a, b top panel); Singh et al. J Lipid Res. 2016, and Singh et al. JCI Insight. 2021 (b, bottom panel). HDL, high-density lipoprotein.

FIGURE 7

Unsaturated fat, when replacing carbohydrate, decreases the secretion rate and catabolic rate of several proteins on specific HDL sizes. Fat, when replacing carbohydrate, decreases the secretion of apoJ and apoL1 on large α0 and of apoA1 on α3 HDL. Fat also decreases the catabolic rates of apoM on α2 and apoA1 on α3 HDL. For apoA2, fat decreases the secretion of apoA2 on α2 by decreasing its rate of conversion from α3. Only the metabolism of LCAT is not altered by diet. Small, grey arrows indicate pathways that are decreased when fat replaced carbohydrate. Large, black arrows indicate pathways that were not altered when fat replaced carbohydrate. Figure summarizing data from Andraski et al. Arterioscler Thromb Vasc Biol. 2019. HDL, high-density lipoprotein.