Abstract
ABSTRACT|Nonalcoholic fatty liver disease (NAFLD) due to excess ectopic fat deposit in the liver of nonalcoholic is a broad spectrum of liver diseases encompassing simple liver steatosis to more complicated and morbid steatohepatitis (NASH) that can lead to cirrhosis and even to hepatocellular carcinoma. Its prevalence in the Western World is about 30%. Insulin resistance dominates the pathogenesis of NAFLD and its complications. Serine phosphorylation of insulin receptor substrate (IRS) has been one of the most common pathways in the establishment of insulin resistance (IR). Novel Protein kinase C (nPKC), is solely activated by diacylglycerol (DAG). Diacylglycerol has been found to be increased in the liver during NAFLD. Several studies have demonstrated a link between vitamin D deficiency, high fructose diet, and NAFLD in human and rodents. The specific aim of this study is to investigate and characterize the isotype of nPKCs involved in the inhibition of IRS-1 pathway using a swine model and to evaluate the effect of vitamin D status on the phenomenon. The Yucatan micro-swine were divided into four experimental groups based on the diet: (i) high cholesterol fed vitamin D-deficient (DEF), (ii) high cholesterol fed vitamin D-sufficient (SUF), high cholesterol fed and vitamin D-supplemented (SUP), and (iv) high cholesterol and high fructose-fed and vitamin D-sufficient (HCHF). We found that DEF and HCHF swine developed IR and presented histological features of NAFLD. HCHF swine were prone to liver fibrosis. PKC-δ was the most relevant novel PKC associated with the pathogenesis of IR and NAFLD. PKC-δ was up-regulated in the liver of both DEF and HCHF swine. PKC-δ was associated with the degradation of IRS-1 in the liver of the DEF swine but not in the liver of the SUF or SUP swine. Even though there were an IR and up-regulation of PKC-δ in the liver of HCHF swine, it was neither associated with the IRS-1 degradation nor with the co-localization of the PKC-δ and p-IRS-1.|These findings suggest that the high cholesterol diet alone does not cause IR or NAFLD in swine; it is either associated with high fructose or with vitamin D deficiency. The combination of high cholesterol and high fructose diet induces IR, NAFLD, and NASH in vitamin D-sufficient swine but not through the degradation of IRS-1.