The role of PPARs in NASH fibrogenesis
I’m going to speak about the role of PPARs (peroxisome proliferator-activated receptors) in NASH (non-alcoholic steatohepatitis) pathogenesis. I think before I answer that question, I want to just point out how important Fibrosis is in NASH. NASH typically occurs on the basis of ongoing information as the name NASH kind of recognizes in the disease progression and fibrosis can be very silent.
So as practitioners we have to be very aware of the possibility that patients who have laboratory or other kinds of indications of NASH potentially may already have Fibrosis and that’s something we may want to test for. Testing that could be based on blood markers and can also be through fibroscan that doesn’t give the staging for the NASH but it’s important to indicate that potentially there is already Fibrosis in these patients. So PPAR agonists are a very exciting potential for NASH for many reasons.
PPAR alpha, gamma and delta particularly are the ones that affect various types from various functions and very briefly alpha, typically PPAR alpha has a role on fat metabolism and hepatocytes and that is one of the features of NASH. PPAR Gamma acts on inflammatory cells and also on some of the Fibrosis related processes particularly on stellate cells. Stellate cells in the liver are the ones that get activated in Fibrosis to put down collagen and all kinds of tissue material that leads to Fibrosis and Cirrhosis. The PPAR gamma in particular can reduce inflammation. So the signals for status activation are attenuated but PPAR gamma also has direct effects on stellate cells by reducing their capacity to put down collagen fibrin and also induce deactivation of the stellate cells, that’s very important. So for that reason, it’s kind of exciting to think that if we can affect and attack all the PPARS at the same time, then we could potentially have multiple benefits at the level of steatosis inflammation and even at Fibrosis.