Activation of M1 macrophages in the nonalcoholic steatohepatitis (NASH) following several external or endogenous factors viz inflammatory stimuli, oxidative stress and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH and NO donor administration inhibits CYP2E1 mediated inflammation with concomitant attenuation of M1 polarization. Since CYP2E1 takes center stage in these studies we use a toxin model of NASH which uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently we use a methionine and choline deficient diet induced rodent NASH model where CYP2E1 role in disease progression has been shown. Results show that CYP2E1 causes M1 polarization bias that includes a significant increase in IL-1β and IL-12 in both models of NASH while CYP2E1 null mice or diallyl sulfide administration prevented it. Administration of GdCl3, a macrophage toxin attenuated both the initial M1 response and subsequent M2 response showing the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, NO donor administration in vivo, that mechanistically inhibited CYP2E1 catalyzed oxidative stress during the entire study in NASH abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization and that inhibition of CYP2E1 catalyzed oxidative stress by NO donor (DETA NONOate) can be a promising therapeutic strategy in NASH.
- The American Society for Pharmacology and Experimental Therapeutics