Abstract
A fructose-fed hamster model of insulin resistance was previously documented to exhibit marked hepatic very low density lipoprotein (VLDL) overproduction. Here, we investigated whether VLDL overproduction was associated with down-regulation of hepatic insulin signaling and insulin resistance. Hepatocytes isolated from fructose-fed hamsters exhibited significantly reduced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates 1 and 2. Phosphatidylinositol 3-kinase activity as well as insulin-stimulated Akt-Ser473 and Akt-Thr308 phosphorylation were also significantly reduced with fructose feeding. Interestingly, the protein mass and activity of protein-tyrosine phosphatase-1B (PTP-1B) were significantly higher in fructose-fed hamster hepatocytes. Chronic ex vivo exposure of control hamster hepatocytes to high insulin also appeared to attenuate insulin signaling and increase PTP-1B. Elevation in PTP-1B coincided with marked suppression of ER-60, a cysteine protease postulated to play a role in intracellular apoB degradation, and an increase in the synthesis and secretion of apoB. Sodium orthovanadate, a general phosphatase inhibitor, partially restored insulin receptor phosphorylation and significantly reduced apoB secretion. In summary, we hypothesize that fructose feeding induces hepatic insulin resistance at least in part via an increase in expression of PTP-1B. Induction of hepatic insulin resistance may then contribute to reduced apoB degradation and enhanced VLDL particle assembly and secretion.
Highlights
Insulin resistance is an extremely common pathophysiological condition that is implicated in the development of a number of important human diseases including type 2 diabetes, atherosclerosis, hypertension, and dyslipidemia [1,2,3,4,5,6,7]
Overproduction of very low density lipoproteins (VLDL)-triglyceride and VLDL-apolipoprotein B (apoB) has been well documented in the insulinresistant state in humans and animal models, few data are available on the underlying molecular mechanisms involved
There are a few studies on the molecular mechanisms that mediate inhibition of apoB secretion following acute insulin exposure; the role of chronic hyperinsulinemia and insulin resistance in VLDL overproduction has been understudied
Summary
Insulin resistance is an extremely common pathophysiological condition that is implicated in the development of a number of important human diseases including type 2 diabetes, atherosclerosis, hypertension, and dyslipidemia [1,2,3,4,5,6,7]. Insulin may regulate VLDL secretion via multiple mechanisms including effects on apoB synthesis and degradation (reviewed in Ref. 22), modulation of MTP expression [23], apoB phosphorylation [24], and apoB mRNA editing [25,26,27]. The inhibitory effect of insulin was attributed to reduced synthesis and increased degradation of apoB in cells incubated with the hormone [24, 37]. Sparks and co-workers [41] demonstrated that in rat hepatocytes, insulin-mediated inhibition of apoB was a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent process. In contrast to acute effects, chronic exposure of primary rat hepatocytes [34] and HepG2 cells [43] to insulin increased apoB secretion. Hepatic insulin resistance may contribute to insensitivity of apoB secretion to the inhibitory actions of insulin
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