Hepatic diacylglycerol-PKC pathway and ER stress as potential mechanisms of fructose-induced glucose intolerance — ASN Events
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Hepatic diacylglycerol-PKC pathway and ER stress as potential mechanisms of fructose-induced glucose intolerance (#234)

Magdalene K Montgomery 1 , Corrine E Fiveash 1 , Jeremy P Braude 1 , Simon HJ Brown 2 , Todd W Mitchell 2 , Nigel Turner 1
  1. University of New South Wales, Kensington, NSW, Australia
  2. School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia

Introduction. Diets enriched in fructose induce lipogenic pathways in the liver, leading to hepatic lipid accumulation and the development of insulin resistance. Previously, we have shown that BALB/c mice are resistant to lipid-induced metabolic deterioration, which is likely related to the absence of hepatic lipid accumulation.

Objective. In this study we have used BALB/c and C57BL/6 (BL6) mice to investigate potential mechanisms underlying fructose-induced hepatic lipid accumulation and its potential impact on glucose tolerance.

Methods. BALB/c and BL6 mice were fed either a standard control diet or a high-fructose diet (30% calories from fructose) for 8 weeks, followed by the determination of glucose tolerance, tissue lipidomics analysis and immunoblotting.

Results. Whereas fructose-fed BL6 mice exhibited typical signs of metabolic deterioration, including hepatic lipid accumulation and glucose intolerance, these metabolic changes were not present in BALB/c mice. Interestingly, while total DAG content in the liver was increased in both strains, polyunsaturated (PUFA) DAG, most likely involved in metabolic deterioration, were reduced in BALB/c, but increased in BL6 mice after fructose-feeding. Increased PUFA-DAG in BL6 mice was accompanied by increased translocation of various PKC isoforms to the membrane, while no PKC activation was observed in BALB/c mice. In addition, fructose-fed BL6 mice exhibited increased endoplasmatic reticulum (ER) stress both in liver and skeletal muscle, whereas these changes were not present in fructose-fed BALB/c mice.

Conclusions. Our findings indicate that hepatic accumulation of polyunsaturated DAG and induction of ER stress pathways are likely major mediators of metabolic deterioration after long-term high-fructose intake.