Role of the Enterocyte in Fructose-Induced Hypertriglyceridaemia

Abstract

Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level; which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL); emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed; including de novo lipogenesis; apolipoprotein B48 and CM-TG production; based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted; including the accurate separation of CM and VLDL. Although the available evidence to date is limited; disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption.

Keywords: apoB48; cardiovascular disease; chylomicron; de novo lipogenesis; fructose; glucagon-like peptide; gluconeogenesis; post-prandial; triglyceride-rich lipoproteins; very low-density lipoprotein.

Figure 1

A schematic representation of the absorption and principal metabolic pathways of fructose and glucose within enterocytes. Fructose and glucose differ in their intracellular metabolism, with glycolytic enzymes subject to control by insulin, ATP and citrate, whereas the phosphorylation of fructose is not controlled. The main metabolic end products are glycogen (glycogenesis), CO₂ (oxidation), lactate, glucose (gluconeogenesis) and fatty acids (de novo lipogenesis). Key enzymes are numbered: (1) fructokinase; (2) aldolase B; (3) hexokinase/glucokinase; (4) phosphofructokinase. Abbreviations: Ac-CoA, acetyl-CoA; DHAP, dihydroxyacetone-phosphate; DNL, de novo lipogenesis; Mal-CoA, malonyl-CoA; MG, methylglyoxal; -P/-diP, phosphate/diphosphate; TG, triglyceride.

Figure 2

The process of de novo lipogenesis (DNL) in humans, where palmitic acid is the major product, which may be further elongated or desaturated to form other fatty acids. Enzymes are numbered: (1) acetyl-CoA carboxylase; (2) fatty acid synthase; (3) fatty acid elongases; (4) Δ9-desaturase.