110 Studies using more powerful ER chaperones are eagerly awaited. Simple hepatic steatosis, which is a benign condition and nonprogressive in the majority of patients, and NASH may reflect different disease entities. Inflammation may precede steatosis in NASH. In contrast, only a small group of patients with simple steatosis might advance toward inflammation and fibrosis. In case of simple steatosis, various protective mechanisms including liver trigylcerides and hyperleptinemia might be operative, thereby protecting the liver from toxic lipid insults. A number

of very diverse parallel processes might contribute to the development of www.selleckchem.com/products/azd-1208.html liver inflammation. Our model suggests that inflammatory mediators derived from various tissues but especially from the gut and adipose tissue could play a central role in the cascade of inflammation, fibrosis, and finally tumor development. Within the adipose and liver tissue, increased lipid storage, lipogenesis, and (adipo)cytokine synthesis may act as stress signals for the ER. XBP1 might reflect an ideal pathway linking many components observed in this disease. Because a high-fat diet is needed in almost all experimental models to induce pathology, it is evident that dietary factors and nutrient sensing are cornerstones of these diseases.113

Whereas genetic factors overall Erismodegib concentration may play a minor role in the current epidemic of obesity, certain genetic factors might well offer explanations for a selleck more progressive disease course in NAFLD.97 Many of the events discussed here might often take place rather in parallel than consecutively, therefore not allowing the exact dissection of the evolution of steatosis and inflammation. Our concept of “multiple parallel hits” might reflect more precisely current knowledge of this metabolic disease and could explain why this disease might also occur in rather lean subjects. We gratefully acknowledge Dr. Arthur Kaser, Medical University Innsbruck, Department of Gastroenterology and Hepatology, for very helpful discussions

and critical reading of the manuscript. “
“Backgound. Skeletal muscle ammonia uptake and concentrations of ammonia are increased in cirrhosis and result in sarcopenia. In the skeletal muscle, ammonia is converted to glutamine and exported extracellularly. Cirrhosis and hyperammonemia are accompanied by reduced plasma and muscle concentrations of leucine and increased plasma concentration of glutamine. Since leucine directly activates mTOR and its downstream signaling, promoting muscle protein synthesis, we determined if leucine transport is maintained and permits rescue of the impaired protein synthesis of hyperammonemia. Methods. Studies were performed in the skeletal muscle from patients with cirrhosis and controls and in differentiated murine C2C12 myotubes during hyperammonemia using protocols established by us.