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

The effect of fructose feeding on intestinal triacylglycerol production and de novo fatty acid synthesis in humans

A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 hours. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (P<0.005) and VLDL-TAG (P=0.003) were greater, and CM-TAG production rate (PR, P=0.046) and CM-TAG fractional catabolic rate (FCR, P=0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (P=0.005) and apoB48 (P=0.039), apoB100 (P=0.013) and NEFA (P=0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (P=0.043) and low-fructose (P=0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase

Role of the enterocyte in fructose-induced hypertriglyceridaemia

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

Dose dependent effects of fructose and glucose on de novo palmitate and glycerol synthesis in an enterocyte cell model

Scope: Fructose exacerbates post-prandial hypertriacylglycerolaemia. This may be partly due to increased enterocyte de novo lipogenesis (DNL). It is unknown whether this is concentration-dependent or whether fructose has a greater effect on lipid synthesis than glucose. The dose-dependent effects of fructose and glucose on DNL and de novo triacylglycerol (TAG)-glycerol synthesis were investigated in an enterocyte model, Caco-2 cells. Methods and results: Caco-2 cells were treated for 96h with 5mM, 25mM or 50mM fructose or glucose, or 12.5mM fructose/12.5mM glucose mix. DNL was measured following addition of [13C2]-acetate to apical media. In separate experiments, [13C6]-fructose and [13C6]-glucose were used to measure DNL and de novo TAG-glycerol synthesis. DNL from [13C2]-acetate was detected following all treatments, with greater amounts in intracellular than secreted (media) samples (all P <0.05). DNL from [13C6]-fructose and [13C6]-glucose was also measurable. Intracellular synthesis was concentration-dependent for both glucose and fructose tracers (P=0.003, P=0.034, respectively) and was higher with 25mM glucose than 25mM fructose (P=0.025). DNL from fructose and glucose was <1%, but up to 70% of de novo TAG-glycerol was synthesised from glucose or fructose. Conclusion: Fructose is not a major source of DNL in Caco-2 cells but contributes substantially to de novo TAG-glycerol synthesis

The effect of fructose on intestinal triacylglycerol production and de novo fatty acid synthesis in humans and in an enterocyte model.

Background: Cardiovascular disease (CVD) remains a significant cause of mortality globally, with a reduction in free sugars consumption a public health target for decreasing disease burden. Fructose raises post-prandial triacylglycerol (TAG) concentrations (risk factor for CVD), relative to glucose or sucrose, possibly due disrupted intestinal TAG metabolism. Aims: Determine whether effects of high-fructose consumption on plasma TAG concentration are explained by intestinal and/or hepatic TAG lipoprotein kinetics, as well as de novo lipogenesis (DNL), in humans and an in vitro model. Methods: Five overweight males consumed drinks containing 30% energy as fructose or complex carbohydrate hourly for 11h on two separate occasions, in a randomised cross-over design (4 week washout). Stable isotopes were given to measure DNL, chylomicron (CM)-TAG and VLDL-TAG kinetics. CM and VLDL were separated according to their apolipoprotein B (apoB) content (Sf>20 fraction). Caco-2 cells were treated (96h) with different fructose and glucose concentrations, or a mixture of sugars (“Mix”), and stable isotopes tracers ([13C6]-fructose; [13C6]-glucose). TAG enrichments were measured by gas chromatography-mass spectrometry. Results: Fructose consumption in comparison to the complex CHO had no effect on either intestinal or hepatic DNL. Intestinal and hepatic DNL were correlated in the fasted (P<0.0001) and fed state (P≤0.004). Plasma TAG (P<0.005) and VLDL-TAG (P=0.003) were greater, and CM-TAG production rate (PR, P=0.046) and fractional catabolic rate (FCR, P=0.073) lower, when fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (P=0.005) and apoB48 (P=0.039), apoB100 (P=0.013) and plasma NEFA (P=0.013) higher in response to fructose. Caco-2 cells utilised fructose and glucose for TAG-palmitate and TAG-glycerol synthesis dose-dependently, with more palmitate derived from glucose after “Mix” treatment (P<0.05). Conclusions: Fructose increased post-prandial TAG concentrations, possibly due to less insulin-mediated lipoprotein metabolism. DNL was unaffected by fructose consumption. This study supports public strategies to restrict dietary free sugars