Carbohydrate-restricted diets:
what is the link with elevated cholesterol?

Following a carbohydrate-restricted diet is often indicated for weight loss and treatment of chronic diseases such as type 2 diabetes.

However, some studies have noted that this dietary change can lead to an increase in so-called “LDL” or “bad” cholesterol, which is an important risk factor in the development of cardiovascular disease.

Given the increasing popularity of carbohydrate-restricted dietand the high mortality from cardiovascular disease, there is a need to understand the mechanisms that impact LDL cholesterol levels and lipid metabolism in response to reduced carbohydrate intake.

Anatol Kontush (Research Director at UMRS 1166 – IHU ICAN)contributed, as co-last author, to the scientific article “The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets”, published on May 20, 2022 in Metabolites.

What is the purpose of this study?

The study is based on self-collected data from 548 individuals following a carbohydrate-restricted diet, corresponding to less than 130 grams per day, with an average carbohydrate intake of 27 grams per day.

An initial analysis identified predictors of increased LDL cholesterol (LDL-C):

  • The body mass index (BMI) of the individual,
  • Metabolic markers of his health,
  • The level of HDL cholesterol (HDL-C),
  • Triglyceride (TG) levels before the diet.

Reminder: Carbohydrates are the main energy nutrients of the human body, divided into two families: simple carbohydrates (fruit, milk, yogurt, chocolate, jams, refined sugar…) and complex carbohydrates (bread, cereals, rice, pasta, legumes, potatoes…)

The analysis revealed that lean people (thus having a low BMI) with a low TG/HDL-C ratio, and following a low-carbohydrate diet, were the most likely to experience increases in their LDL cholesterol levels.

This allowed us to isolate a subset of 100 “Lean Mass Hyper-responder” (LMHR) individuals with particularly large increases in both LDL and HDL cholesterol levels in the context of carbohydrate restriction, combined with low triglyceride levels. The mechanism was reversible with reintroduction of carbohydrates into the diet, and no significant genetic factors were revealed in testing.

The objective of this scientific publication is therefore to provide an explanation for the LMHR phenotype, using the “Lipid Energy Model” (LEM).

What is Lipid Energy Model? (LEM) (LEM)

The Lipid Energy Model (LEM) is a hypothesis that under conditions of carbohydrate restriction and the presence of fat in the subcutaneous cellular tissue, it resides greater reliance on fat as a metabolic substrate, as provided by triglyceride-rich lipoproteins, including VLDL (very low density lipoproteins) synthesized and secreted by the liver

Increase in LDL-C and HDL-C by lipoprotein lipase

In the presence of increased VLDL synthesis and secretion, lipoprotein lipase (LPL) activity releases free fatty acids (FFA = non-esterified fatty acids = NEFA) to adipocytes and oxidative tissue. As TGs are lipolyzed, VLDL shrinks with the loss of surface residues (including cholesterol, phospholipids, and apolipoproteins) to HDL-accepting particles and is then catabolized into LDL, resulting in an increase in LDL particle mass, LDL-C, HDL particle mass, and HDL-C. Source: Metabolites 2022, 12(5), 460.

This increased dependence leads to increased hepatic secretion of VLDL and lipolysis of VLDL by lipoprotein lipase with high production of free fatty acids (FFA), which are an important source of energy for the body.

Then, the peripheral absorption of these acids increases, as does the accumulation in the circulation of LDL (which is the end product of VLDL lipolysis) and the level of LDL-C. In parallel, cholesterol-containing fragments of the VLDL surface are released and transferred to HDL, resulting in marked elevation of HDL-C. Finally, circulating triglyceride levels decrease as a result of lipolysis. According to the Lipid Energy Model (LEM), this pathway is particularly active in lean individuals with a low baseline TG/HDL-C ratio, because these individuals are characterized by particularly efficient VLDL lipolysis.

Know more about Lipid Energy Model (LEM) here.

The Lipid Energy Model (LEM)

(A) In the context of carbohydrate restriction, (1) glycogen depletion and (2) changes in circulating hormones stimulate hormone-sensitive lipase (HSL)-mediated secretion of free fatty acids (FFAs = NEFAs) from adipocytes to supply oxidative tissues. (3) The liver captures circulating NEFA and repackages it into triglycerides (TG), (4) secreted on board VLDL (5) Increased lipoprotein lipase (LPL)-mediated VLDL destruction generates increased LDL-C and HDL-C. (B) The magnitude of carbohydrate restriction, adiposity, and energy expenditure each contribute as independent variables to the degree of LPL-mediated VLDL turnover and, therefore, to the magnitude of variation in the components of the triad. Source: Metabolites 2022, 12(5), 460.

What is the conclusion of this research work?

The research work carried out concludes that the Lipid Energy Model (LEM) could explain the inverse association observed between the individual’s BMI (Body Mass Index) and the change in his or her LDL cholesterol level in a context of carbohydrate consumption restriction. Indeed, high levels of LDL cholesterol are an important cardiovascular risk factor. This work therefore calls for further research to assess this risk in individuals on low-carbohydrate diets.

This model provides specific and testable predictions to be evaluated in future studies to better understand the mechanisms underlying the change in LDL cholesterol on low-carbohydrate diets. This will advance our knowledge of lipid and lipoprotein dynamics in human metabolism.

The authors of the publication: Nicholas G.Norwitz, Adrian Soto-Mota, Bob Kaplan, David S. Ludwig, Matthieu Boudoff, Anatol Kontush, David Felman.

Discover the complete scientific publication here.

The excellence of the ICAN Omics lipidomics platform

The ICAN IHU has a “lipidomics” platform specialized in metabolic diseases (NASH, T2DM, atherosclerosis, hypercholesterolemia, cardiomyopathy…) which combines metabolomic and lipidomic approaches and bioinformatics tools. Thanks to cutting-edge technologies, it allows the identification of new biomarkers to improve the prediction of metabolic pathologies

Located at the Pitié-Salpêtrière Hospital in Paris, our platform has been awarded the IBiSA label(Infrastructures in Biology, Health and Agronomy) label in 2021.