Interleukin-18-deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease and steatohepatitis

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• 作者：Kyosuke Yamanishi^a ; ^b ; Seishi Maeda^c ; Sachi Kuwahara-Otani^c ; Yuko Watanabe^b ; Momoko Yoshida^b ; ^d ; Kaoru Ikubo^a ; Daisuke Okuzaki^e ; ^f ; Yosif El-Darawish^g ; Wen Li^g ; Keiji Nakasho^h ; Hiroshi Nojima^e ; ^f ; Hiromichi Yamanishi^b ; Tetsu Hayakawa^g ; Haruki Okamura^g ; Hisato Matsunaga^a ; ^{hisa1311@hyo-med.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Apoa4 ; apolipoprotein A-IV ; BMAL1 ; brain and muscle Arnt-like protein ; Camk2b ; calcium/calmodulin-dependent protein kinase II beta ; Ccnd1 ; cyclin D1 ; CLOCK ; circadian locomotor output cycles kaput ; G6pc ; glucose-6-phosphatase ; catalytic ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; Gnrh1 ; gonadotropin-releasing hormone 1 ; HDL ; high-density-lipoprotein ; H-cho ; HDL cholesterol ; Htr2b ; 5-hydroxytryptamine (serotonin) receptor 2B ; IL-18 ; interleukin 18 ; Il18 ; interleukin 18 ; Il18&minus ; /&minus
• 刊名：Translational Research
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：173
• 期：Complete
• 页码：101-114.e7
• 全文大小：3369 K

文摘

We investigated potential pathophysiological relationships between interleukin 18 (IL-18) and dyslipidemia, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Compared with Il18^+/+ mice, IL-18 knockout (Il18^−/−) mice developed hypercholesterolemia and hyper-high-density-lipoprotein-cholesterolemia as well as hypertriglyceridemia as they aged, and these disorders occurred before the manifestation of obesity and might cause secondary NASH. The analyses of molecular mechanisms involved in the onset of dyslipidemia, NAFLD, and NASH in Il18^−/− mice identified a number of genes associated with these metabolic diseases. In addition, molecules related to circadian rhythm might affect these extracted genes. The intravenous administration of recombinant IL-18 significantly improved dyslipidemia, inhibited the body weight gain of Il18^+/+ mice, and prevented the onset of NASH. The expression of genes related to these dysfunctions was also affected by recombinant IL-18 administration. In conclusion, this study demonstrated the critical function of IL-18 in lipid metabolism and these findings might contribute to the progress of novel treatments for NAFLD or NASH.