Abstract
A high fat Western-style diet leads to hepatic steatosis that can progress to steatohepatitis and ultimately cirrhosis or liver cancer. The mechanism that leads to the development of steatosis upon nutritional overload is complex and only partially understood. Using click chemistry-based metabolic tracing and microscopy, we study the interaction between Kupffer cells and hepatocytes ex vivo. In the early phase of steatosis, hepatocytes alone do not display significant deviations in fatty acid metabolism. However, in co-cultures or supernatant transfer experiments, we show that tumor necrosis factor (TNF) secretion by Kupffer cells is necessary and sufficient to induce steatosis in hepatocytes, independent of the challenge of hepatocytes with elevated fatty acid levels. We further show that free fatty acid (FFA) or lipopolysaccharide are both able to trigger release of TNF from Kupffer cells. We conclude that Kupffer cells act as the primary sensor for both FFA overload and bacterial lipopolysaccharide, integrate these signals and transmit the information to the hepatocyte via TNF secretion. Hepatocytes react by alteration in lipid metabolism prominently leading to the accumulation of triacylglycerols (TAGs) in lipid droplets, a hallmark of steatosis.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries [1,2,3] presenting with a wide range of pathologies
This includes steatosis, which manifests in an excessive accumulation of lipid droplets (LDs) in hepatocytes, steatohepatitis, which is a combination of steatosis and liver inflammation, and liver cirrhosis, i.e., excessive fibrosis with loss of hepatocytes and liver function
DefiningDuring the factors that trigger development of initial macroscopic showed hepatic symptoms of a steatosis major signs ofalong inflammatory pathologicalobesity, signs inmice the liver during metabolic overload
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries [1,2,3] presenting with a wide range of pathologies This includes steatosis, which manifests in an excessive accumulation of lipid droplets (LDs) in hepatocytes, steatohepatitis, which is a combination of steatosis and liver inflammation, and liver cirrhosis, i.e., excessive fibrosis with loss of hepatocytes and liver function. The “first hit” is characterized by a reversible steatosis, thought to originate from excess amounts of free fatty acid (FFA), which are esterified to triacylglycerol (TAG) This links NAFLD to obesity, in which FFA are strongly elevated [5,6]. Contradicting the two-hit model, it was recently shown that interleukin(IL)-6
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