Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1

Myeloid cell and hepatocyte IKK may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of nonalcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKK deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKK deficiency (Ikbkbhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male Ikbkbhep mice having worst NASH and lowest plasma estradiol levels. LXR is enriched to LXRE on Sult1e1 promoter in male WT and Ikbkbhep mice with NASH, and a Sult1e1 promoter activity is increased by LXR and its ligand and augmented by expression of a S32A mutant of IB. These results demonstrate striking gender differences in regulation by IKK of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKK is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients.