Hepatocyte‐Specific Knockout of Na⁺/H⁺ Exchanger‐1 Does Not Ameliorate <scp>NASH</scp>‐Associated Liver Damage in Mice

ABSTRACT Non‐alcoholic fatty liver disease (NAFLD) is the fastest‐growing liver‐related cause of mortality, affecting about 25% of the adult world population. Despite this, fundamental questions regarding the underlying mechanisms remain incompletely answered. In mice, whole‐body knockout (KO) of Na + /H + exchanger NHE1 (SLC9A1) was suggested to be protective against NASH. However, the translatability of this finding is confounded by the fact that global NHE1 KO affects ubiquitous processes in tissues outside of the liver. Here, we aimed to determine the role of hepatocyte NHE1 in NAFLD. We generated a hepatocyte‐specific NHE1 KO (NHE1 HKO) mouse and determined the impact of NHE1 loss on liver metabolism and NAFLD characteristics following methionine–choline‐deficient (MCD) diet. Loss of hepatocyte NHE1 does not protect against NAFLD development, but rather seems to impair basal ROS balance in the mouse liver.