Absence of CD36 alters systemic vitamin A homeostasis

Fatty acid translocase (CD36) is a scavenger receptor with multiple ligands and diverse physiological actions. We recently reported that alcohol-induced hepatic retinoid mobilization is impaired in Cd36−/− mice, leading us to hypothesize that CD36 has a novel role in hepatic vitamin A mobilization. Given the central role of the liver in systemic vitamin A homeostasis we also postulated that absence of CD36 would affect whole-body vitamin A homeostasis. We tested this hypothesis in aging wild type and Cd36−/− mice, as well as mice fed a vitamin A-deficient diet. In agreement with our hypothesis, Cd36−/− mice accumulated hepatic retinyl ester stores with age to a greater extent than wild type mice. However, contrary to expectations, Cd36−/− mice consuming a vitamin A-deficient diet mobilized hepatic retinoid similar to wild type mice. Interestingly, we observed that Cd36−/− mice had significantly reduced white adipose tissue retinoid levels compared to wild type mice. In conclusion, we demonstrate that the absence of CD36 alters whole-body vitamin A homeostasis and suggest that this phenotype is secondary to the impaired chylomicron metabolism previously reported in these mice.

Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism

The mechanisms underlying the oversecretion of apolipoprotein (apo)B-48-containing triglyceride-rich lipoproteins (TRL) in insulin-resistance (IR) states in humans remain to be fully understood. The objective of this study was to evaluate the association between the plasma levels of insulin and glucose and the intestinal expression of key genes involved in chylomicron metabolism in a large sample of nondiabetic men displaying various degrees of IR. Duodenal biopsies were obtained by gastroduodenoscopy in 127 men free of intestinal disease. Gene expression was measured using quantitative PCR in duodenal samples. Plasma insulin and glucose concentrations were measured in the fasting state. Postprandial TRL apoB-48 kinetics were measured using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in a subgroup of 75 subjects maintained in a constant fed state. Plasma insulin levels were negatively associated with intestinal expression of ACS1 (standard β = −0.20, P = 0.007), DGAT1 (β = −0.18, P = 0.001), DGAT2 (β = −0.20, P = 0.02), and MTP (β = −0.27, P = 0.0005), whereas glucose levels were positively associated with MTP expression (β = 0.15, P = 0.04) independent of age, BMI, waist circumference, dietary intake, and duodenal expression of SREBP1c. Insulin levels, but not glucose concentrations, were positively correlated with postprandial TRL apoB-48 production rate ( r = 0.24, P = 0.04) and pool size ( r = 0.27, P = 0.03). In conclusion, plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism. These results suggest that alterations in intestinal lipoprotein metabolism associated with IR may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency. NEW & NOTEWORTHY We demonstrate that plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism in men. For instance, intestinal expression of MTP is negatively associated with plasma insulin concentrations and positively associated with plasma glucose concentrations. Alterations in intestinal lipoprotein metabolism associated with insulin resistance may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency.

Dietary fat and physiological determinants of plasma chylomicron remnant homoeostasis in normolipidaemic subjects: insight into atherogenic risk

TAG depleted remnants of postprandial chylomicrons are a risk factor for atherosclerosis. Recent studies have demonstrated that in the fasted state, the majority of chylomicrons are small enough for transcytosis to arterial subendothelial space and accelerate atherogenesis. However, the size distribution of chylomicrons in the absorptive state is unclear. This study explored in normolipidaemic subjects the postprandial distribution of the chylomicron marker, apoB-48, in a TAG-rich lipoprotein plasma fraction (Svedberg flotation rate (Sf>400), in partially hydrolysed remnants (Sf 20–400) and in a TAG-deplete fraction (Sf<20), following ingestion of isoenergetic meals with either palm oil (PO), rice bran or coconut oil. Results from this study show that the majority of fasting chylomicrons are within the potentially pro-atherogenic Sf<20 fraction (70–75 %). Following the ingestion of test meals, chylomicronaemia was also principally distributed within the Sf<20 fraction. However, approximately 40 % of subjects demonstrated exaggerated postprandial lipaemia specifically in response to the SFA-rich PO meal, with a transient shift to more buoyant chylomicron fractions. The latter demonstrates that heterogeneity in the magnitude and duration of hyper-remnantaemia is dependent on both the nature of the meal fatty acids ingested and possible metabolic determinants that influence chylomicron metabolism. The study findings reiterate that fasting plasma TAG is a poor indicator of atherogenic chylomicron remnant homoeostasis and emphasises the merits of considering specifically, chylomicron remnant abundance and kinetics in the context of atherogenic risk. Few studies address the latter, despite the majority of life being spent in the postprandial and absorptive state.

Abstract 237: The First Direct Measure of Chylomicron Metabolism in Heart Reveals a Reciprocal Balance Between Mitochondrial Oxidation of Fats From Chylomicron vs Albumin Sources

Nearly all studies of fat metabolism in healthy and diseased heart are based on albumin sources of fat, even though lipoproteins (chylomicrons, VLDL) are thought to be a major source of fat. If there are distinct differences in uptake, oxidation, and storage of fatty acids (FA) from lipoproteins compared to albumin sources, then our understanding of disease is far from complete. This study provides the very first investigation of the fate of 13C labeled FA from chylomicrons (CM) in heart, with quantified results of the direct competition between CM-FA vs albumin-FA to support mitochondrial ATP synthesis. Chylomicrons were biosynthetically labeled with 13C-oleate by delivering to the duodenum of rat either (a) emulsified in olive oil, or (b) incorporated into micelles. The labeled chylomicrons were collected as lymph via the thoracic duct for six hours. The olive oil approach, used traditionally to prepare CM to contain radiolabeled fats, resulted in a trace fraction of 13C-labeled FA (<2%). The micelle approach enabled 50% enrichment of CM-FA store. Metabolic studies: Isolated rat hearts were perfused with KH buffer containing 13C-chylomicrons, FA free albumin, and glucose; or 13C-chylomicrons, unlabeled oleate complexed to albumin (equimolar FA from CM and albumin; 0.4 mM), and glucose. Hearts were freeze-clamped, and FA oxidation was assessed via high resolution 13C NMR of heart samples. CM-FA provided 50 ± 5 % of the acetyl CoA to support citric acid cycle synthesis of ATP when FA free albumin was used. In the presence of albumin-FA, only 12 ± 2% of acetyl CoA entering the cycle was from the CM-FA. These direct observations of the competition between CM-FA vs albumin-FA counter prior interpretations based on indirect measures. Those studies suggested no change in CM-FA oxidation when albumin-FA was added. Our novel approach enables direct measurements of CM-FA and albumin-FA oxidation in the mitochondria of intact hearts. The uptake and distribution of fat from either exogenous source were found to contribute to a common intracellular source of activated FA, with mitochondrial oxidation being proportional to the availability of the FA source. Importantly, this new evidence for a common pool significantly simplifies our metabolic paradigm of cardiac disease.