| First Author | Matsushita N | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 8 | Pages | e0181052 |
| PubMed ID | 28797077 | Mgi Jnum | J:245984 |
| Mgi Id | MGI:5914139 | Doi | 10.1371/journal.pone.0181052 |
| Citation | Matsushita N, et al. (2017) Gender difference in NASH susceptibility: Roles of hepatocyte Ikkbeta and Sult1e1. PLoS One 12(8):e0181052 |
| abstractText | Myeloid cell and hepatocyte IKKbeta may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKbeta 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 IKKbeta deficiency (IkbkbDeltahep) 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 IkbkbDeltahep mice having worst NASH and lowest plasma estradiol levels. LXRalpha is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbDeltahep mice with NASH, and a Sult1e1 promoter activity is increased by LXRalpha and its ligand and augmented by expression of a S32A mutant of IkappaBalpha. These results demonstrate striking gender differences in regulation by IKKbeta of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKbeta 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. |
