Diabetes of the liver: the link between nonalcoholic fatty liver disease and HFCS-55.
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance. It is also a predisposing factor for type 2 diabetes. Dietary factors are believed to contribute to all three diseases. NAFLD is characterized by increased intrahepatic fat and mitochondrial dysfunction, and its etiology may be attributed to excessive fructose intake. Consumption of high fructose corn syrup-55 (HFCS-55) stands at up to 15% of the average total daily energy intake in the United States, and is linked to weight gain and obesity. The aim of this study was to establish whether HFCS-55 could contribute to the pathogenesis of NAFLD, by examining the effects of HFCS-55 on hepatocyte lipogenesis, insulin signaling, and cellular function, in vitro and in vivo. Exposure of hepatocytes to HFCS-55 caused a significant increase in hepatocellular triglyceride (TG) and lipogenic proteins. Basal production of reactive oxygen metabolite (ROM) was increased, together with a decreased capacity to respond to an oxidative challenge. HFCS-55 induced a downregulation of the insulin signaling pathway, as indicated by attenuated (ser473)phosphorylation of AKT1. The c-Jun amino-terminal kinase (JNK), which is intimately linked to insulin resistance, was also activated; and this was accompanied by an increase in endoplasmic reticulum (ER) stress and intracellular free calcium perturbation. Hepatocytes exposed to HFCS-55 exhibited mitochondrial dysfunction and released cytochrome C (CytC) into the cytosol. Hepatic steatosis and mitochondrial disruption was induced in vivo by a diet enriched with 20% HFCS 55; accompanied by hypoadiponectinemia and elevated fasting serum insulin and retinol-binding protein-4 (RBP4) levels. Taken together our findings indicate a potential mechanism by which HFCS-55 may contribute to the pathogenesis of NAFLD.
Collison
Kate S
KS
Cell Biology and Diabetes Research Unit, Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. kate@kfshrc.edu.sa
Saleh
Soad M
SM
Bakheet
Razan H
RH
Al-Rabiah
Rana K
RK
Inglis
Angela L
AL
Makhoul
Nadine J
NJ
Maqbool
Zakia M
ZM
Zaidi
Marya Zia
MZ
Al-Johi
Mohammed A
MA
Al-Mohanna
Futwan A
FA
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001835:Body Weight; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000473:pathology; D005234:Fatty Liver / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005632:Fructose / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000473:pathology; D018384:Oxidative Stress; D013549:Sweetening Agents / Q000633:toxicity*; D003313:Zea mays
D015415:Biomarkers; D013549:Sweetening Agents; D005632:Fructose