NAFLD and fatty liver is the accumulation
NAFLD and fatty liver is the accumulation of fat and cholesterol in hepatocytes. NAFLD is one of the most common liver diseases in the USA and worldwide. NAFLD is associated with obesity, inflammation and insulin resistance. Fat accumulation in the liver is due to the uptake and synthesis (intake) of fats being greater than β-oxidation and secretion via very low density lipoprotein (export). A small percentage of patients with NAFLD will go on to develop NASH, which increases the risk of cirrhosis and liver cancer. Diet is a major factor in NAFLD development. A Western-type diet high in saturated fats and fructose, which stimulates lipogenesis, appears to overload the ability of the liver to oxidize and secrete fats. Saturated fats and fructose are associated with an increase in ML365 of inflammatory markers, which can disrupt the normal bile acid- and insulin-activated cell signaling pathways that regulate the metabolism of glucose, sterols and fats in the liver. CBA-activated nuclear SphK2 appears to be a key mechanism by which liver hepatocytes increase the oxidation and secretion of fats (Fig. 4, Table 1). Moreover, up-regulation of SphK2 expression appears to increase AKTS473 phosphorylation and enhance hepatic glucose metabolism. It is not known if inflammation suppresses hepatic signaling from CBA > S1PR2 > SphK2 > S1P synthesis and gene regulation.
Future directions, S1PR2, and liver cancers Future approaches for the prevention and treatment of NAFLD might include ways to up-regulate hepatic expression of nuclear SphK2 by developing specific agonists for S1PR2, which would up-regulate expression of nuclear SphK2 and increase β-oxidation of fatty acids and secretion of lipids and cholesterol via very-low-density lipoprotein. However, long-term use of such agonists may lead to the proliferation of cholangiocytes and other intestinal epithelial cells, and to an increased risk of cancers of the liver and gastrointestinal tract. In this regard, it has been reported that CBAs stimulate the proliferation of rodent and human cholangiocarcinoma cell lines. Moreover, S1PR2 and SphK2 are highly expressed in human cholangiocarcinoma cancers, and inhibition of S1PR2 by a chemical antagonist (JTE-013) or knockdown of S1PR2 by shRNA significantly inhibits the proliferation of cholangiocarcinoma cell lines. Finally, the S1PR2/SphK2 cell signaling pathway illustrates the physiologic link between nutrient metabolism and cell proliferation. Efforts should be made to ascertain if other cell signaling pathways are activated via S1PR2.
Conflict of interest
Acknowledgements This work was supported by the US National Institutes of Health (grants R01DK57543 and R01DK104893).
Introduction Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic fat accumulation (steatosis) that is not caused by alcohol consumption. NAFLD is a common liver disease and affects ∼30% of the Western population. Currently, simple hepatic steatosis does not require clinical treatment. However, in some patients it may progress to nonalcoholic steatohepatitis (NASH), which is a more debilitating form of NAFLD characterized by the presence of hepatocellular injury and inflammation. Patients with NASH have a significantly increased risk of developing fibrosis, cirrhosis, liver cancer and liver failure. In addition, patients with NASH have a significantly higher risk of cardiovascular diseases (CVD), which are the leading cause of morbidity and mortality among these patients. NASH pathogenesis is incompletely understood and is considered a result of complex interactions between genetic and environmental factors. Patients with NASH are often obese and diabetic and commonly possess other features of metabolic syndrome, such as insulin resistance, dyslipidemia and hypertension. It is thought that over-nutrition and obesity cause adipocyte stress and dysfunction, leading to inflammatory infiltration and adipose insulin resistance. As a result, uncontrolled lipolysis causes increased free fatty acid release and fatty acid lipotoxicity in non-conventional fat storage tissues, such as the skeletal muscle, pancreas and liver. Adipose-derived fatty acids serve as a major source of hepatic fat in NAFLD. Increased hepatic fat accumulation in the presence of insulin resistance further promotes hepatic triglyceride overproduction, which is a key contributing factor to dyslipidemia and higher CVD risk. Unfortunately, there are no approved therapies for NASH. Patients who develop end-stage liver disease require a liver transplantation. New therapeutic interventions that treat both liver-related and cardiovascular-related complications in patients with NASH are still needed.