Multiple pathways of programmed cell death are important in liver homeostasis. Hepatocyte death is associated with progression of nonalcoholic fatty liver disease (NAFLD) and inhibition of apoptosis partially protects against liver injury in response to high fat diets (HFD). However, the contribution of necroptosis, a caspase-independent pathway of cell death, to HFD-induced liver injury is not known. Wild-type C57BL/6 and receptor interacting protein (RIP) 3−/− mice were randomized to chow or HFD. HFD-fed C57BL/6 mice increased expression of RIP3, the master regulator of necroptosis, as well as phosphorylated mixed lineage kinase domain-like (pMLKL), an effector of necroptotic cell death, in liver. HFD did not increase pMLKL in RIP3−/− mice. HFD increased fasting insulin and glucose, as well as glucose intolerance, in C57BL/6 mice. RIP3−/− were glucose intolerant even on chow diets; HFD further increased fasting glucose and insulin, but not glucose intolerance. HFD also increased hepatic steatosis, plasma ALT activity, inflammation, oxidative stress and hepatocellular apoptosis in wild-type mice; these responses were exacerbated in RIP3−/− mice. Importantly, increased inflammation and injury was associated with early indicators of fibrosis in RIP3−/− compared to C57BL/6 mice. Culture of AML12 hepatocytes with palmitic acid increased cytotoxicity via apoptosis and necrosis. Inhibition of RIP1 with necrostatin-1 or siRNA knock-down of RIP3 reduced palmitic acid-induced cytotoxicity.
Conclusion
Absence of RIP3, a key mediator of necroptosis, exacerbated HFD-induced liver injury, associated with increased inflammation and hepatocyte apoptosis, as well as early fibrotic responses. These findings indicate that shifts in the mode of hepatocellular death can influence disease progression and have therapeutic implications because manipulation of hepatocyte cell death pathways is being considered as a target for treatment of NAFLD.
Markers of the extrinsic pathway of hepatocyte apoptosis are elevated in children with NASH. sFasL and the NASH apoptosis score are potential novel biomarkers for NASH.
The COVID-19 pandemic is posing a worldwide challenge to control and contain. SARS-CoV-2 is a highly infectious virus. Health care providers at the front lines are at high risk of getting the infection and the risk applies also to laboratory personnel as they deal with specimens that might be contaminated with infectious materiel. Cytopathology teams specifically are at high risk of dealing with contaminated material because of patients encounter during fine-needle aspiration biopsies or Rapid On-Site Evaluation (ROSE) for adequacy. In our article, we discuss alternative safer staining methods to the widely used Diff-Quick stain that can be utilized for ROSE to decrease the risk of viral exposure during the current COVID-19 pandemic.
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