Date Published: August 10, 2017
Publisher: Public Library of Science
Author(s): Noriko Matsushita, Mohamed T. Hassanein, Marcos Martinez-Clemente, Raul Lazaro, Samuel W. French, Wen Xie, Keane Lai, Michael Karin, Hidekazu Tsukamoto, Anna Alisi.
Myeloid cell and hepatocyte IKKβ 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 IKKβ 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 IKKβ deficiency (IkbkbΔhep) 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 IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKβ of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKβ 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.
Non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) is the most prevalent liver disease in the world and is commonly associated with obesity and insulin resistance (IR) [1–3]. Although the genetic and nutrient-deficient models such as that with choline and methionine deficient diet, have been widely used for experimental studies, it is well recognized that these models do not reflect a natural history or course of NAFLD/NASH seen in patients. To this end, different models have recently been developed which emphasize the common etiological backgrounds such as overnutrition  and a diet high in cholesterol and saturated fat (HCSF) [5–8].
The present study demonstrates the gender-specific, differential regulatory roles of IKKβ in myeloid cells and hepatocytes in obesity, IR, and NASH induced by HCFD in mice as summarized in Table 2. Key findings can be summarized as follows. Firstly, HCFD feeding to adult C57Bl/6 mice results in a wide spectrum of metabolic syndrome as previously reported , including obesity, visceral adiposity, hyperglycemia, global IR and NASH, and these complications are generally more pronounced in males than females. Secondly, although myeloid IKKβ deficiency corrects obesity and visceral adiposity in female but not male mice, it ameliorates fasting hyperglycemia, global IR, and steatohepatitis in both genders. Thirdly, hepatocyte IKKβ deficiency aggravates all of these sequela in male, but not in female mice. These gender specific differences are closely associated with: 1) lower plasma adiponectin levels in males regardless of diet or genotype; 2) lower p-AMPK and higher nSRBP-1c in the livers of males fed HCFD compared to females; 3) marked reductions in plasma adiponectin, hepatic p-AMPK and PPARδ levels and conspicuous increases in nSREBP-1c and p-JNK1/2 in aggravated NASH in male hepatic IKKβ deficient mice fed HCFD; 4) lower hepatic M2 gene (Arg1 and Chi3l3) expression in males than females regardless of diet or genotype; 5) further repression of these M2 genes in aggravated NASH in male hepatic IKKβ deficient mice; 6) inflammation in WAT associated with HCFD-induced NASH which is ameliorated by myeloid IKKβ deficiency in females and aggravated by hepatic IKKβ deficiency in males.