Abstract
Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.
Highlights
Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles
Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apolipoprotein B48 (apoB48) secretion. These findings further suggest that intestinal overproduction of apoB48 lipoproteins should be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state
In the present study we have demonstrated overproduction of intestinal apoB48-containing lipoproteins in the FF Syrian golden hamster, a model of dietary-induced insulin resistance and hypertriglyceridemia
Summary
Animal Protocols—Male Syrian golden hamsters (Mesocricetus auratus, Charles River, Montreal, QC, Canada) were housed in pairs and were given free access to food and water. The protocol developed for isolation of epithelial cells from hamster small intestine was based on that described by Perreault and Beaulieu [41]. Preliminary experiments (n ϭ 4) demonstrated that this method of feeding resulted in constant Sf Ͼ 400 (i.e. large TG-rich lipoprotein (TRL)) and Sf 100 – 400 (small TRL), TG and apoB48 concentrations between 60 and 80 min (i.e. the time period of measurement of intestinal particle production rates following administration of Triton). Large and small apoB48 and TG secretion rates were performed by multiplying the slope of the concentration increase of apoB48 (in g/ml/min) and TG (in mol/ml/min), respectively, over time by the intravascular distribution volume estimated as 3.8 ml/100 g body weight, as previously described [39]. Fractions 2– 4 and 5–7 were considered intermediate density lipoprotein/low density lipoprotein (d ϭ 1.02–1.063 g/ml) and high density lipoprotein (1.063–1.1 g/ml), respectively
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