Obesity and type 2 diabetes are associated with increased lipogenesis in the liver. This results in fat accumulation in hepatocytes, a condition known as hepatic steatosis, which is a form of nonalcoholic fatty liver disease (NAFLD), the most common cause of liver dysfunction in the United States. Carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, has emerged as a major player in the development of hepatic steatosis in mice. However, the molecular mechanisms enhancing its transcriptional activity remain largely unknown. In this study, we have identified the histone acetyltransferase (HAT) coactivator p300 and serine/threonine kinase salt-inducible kinase 2 (SIK2) as key upstream regulators of ChREBP activity. In cultured mouse hepatocytes, we showed that glucose-activated p300 acetylated ChREBP on Lys672 and increased its transcriptional activity by enhancing its recruitment to its target gene promoters. SIK2 inhibited p300 HAT activity by direct phosphorylation on Ser89, which in turn decreased ChREBP-mediated lipogenesis in hepatocytes and mice overexpressing SIK2. Moreover, both liver-specific SIK2 knockdown and p300 overexpression resulted in hepatic steatosis, insulin resistance, and inflammation, phenotypes reversed by SIK2/p300 co-overexpression. Finally, in mouse models of type 2 diabetes and obesity, low SIK2 activity was associated with increased p300 HAT activity, ChREBP hyperacetylation, and hepatic steatosis. Our findings suggest that inhibition of hepatic p300 activity may be beneficial for treating hepatic steatosis in obesity and type 2 diabetes and identify SIK2 activators and specific p300 inhibitors as potential targets for pharmaceutical intervention.

The gluten-free (GF) products market represents one of the most prosperous markets in the field of food and beverages in the immediate future. Historically, counselling for celiac disease has focused on the absence of gluten in foods, however the nutritional quality of GF foodstuffs is an important aspect to consider. The aim of the present work was to compare the nutritional composition of the 206 GF rendered products most consumed in Spain, against the composition of 289 equivalent foods with gluten, and to make a comparison between the diet including GF products and the same diet with equivalent products with gluten in a 58 adult celiac population. The results of the present collaborative study pointed out differences in calorie, macronutrient, fiber, sodium, salt and cholesterol content between GF rendered and gluten-containing foodstuffs. Thus, calorie and nutrient intake in a GF diet is different when compared to its equivalent diet with gluten. Following a diet based on GF products could suppose a nutritional imbalance for celiac patients as well as for non-celiacs who follow a diet that includes many GF rendered foodstuffs.

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