Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models
Toshiya Matsukawa, Takashi Yagi, Tohru Uchida, Mashito Sakai, Masaru Mitsushima, Takao Naganuma, Hiroyuki Yano, Yuka Inaba, Hiroshi Inoue, Keisuke Yanagida, Masaaki Uematsu, Kazuki Nakao, Harumi Nakao, Atsu Aiba, Yoji Nagashima, Tetsuya Kubota, Naoto Kubota, Yoshihiko Izumida, Naoya Yahagi, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Shun-ichiro Asahara, Yoshiaki Kido, Hideo Shindou, Michiko Itoh, Yoshihiro Ogawa, Shiro Minami, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Masato Kasuga, Michihiro Matsumoto
Toshiya Matsukawa, Takashi Yagi, Tohru Uchida, Mashito Sakai, Masaru Mitsushima, Takao Naganuma, Hiroyuki Yano, Yuka Inaba, Hiroshi Inoue, Keisuke Yanagida, Masaaki Uematsu, Kazuki Nakao, Harumi Nakao, Atsu Aiba, Yoji Nagashima, Tetsuya Kubota, Naoto Kubota, Yoshihiko Izumida, Naoya Yahagi, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Shun-ichiro Asahara, Yoshiaki Kido, Hideo Shindou, Michiko Itoh, Yoshihiro Ogawa, Shiro Minami, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Masato Kasuga, Michihiro Matsumoto
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Research Article Hepatology Metabolism

Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models

Abstract

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor–deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

Authors

Toshiya Matsukawa, Takashi Yagi, Tohru Uchida, Mashito Sakai, Masaru Mitsushima, Takao Naganuma, Hiroyuki Yano, Yuka Inaba, Hiroshi Inoue, Keisuke Yanagida, Masaaki Uematsu, Kazuki Nakao, Harumi Nakao, Atsu Aiba, Yoji Nagashima, Tetsuya Kubota, Naoto Kubota, Yoshihiko Izumida, Naoya Yahagi, Hiroyuki Unoki-Kubota, Yasushi Kaburagi, Shun-ichiro Asahara, Yoshiaki Kido, Hideo Shindou, Michiko Itoh, Yoshihiro Ogawa, Shiro Minami, Yasuo Terauchi, Kazuyuki Tobe, Kohjiro Ueki, Masato Kasuga, Michihiro Matsumoto

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Figure 6

Hepatic FASN deficiency in Mc4r-KO mice ameliorates NAFLD and diabetes.

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Hepatic FASN deficiency in Mc4r-KO mice ameliorates NAFLD and diabetes. ...
(A–E) BW (n = 8) and 24-hour food intake (n = 5) (A), macroscopic appearance of the liver (B), liver weight (n = 5) (C), H&E and Oil Red O staining of liver sections (D), and hepatic triglyceride and cholesterol levels in the fed state (n = 5) (E) for 16- to 19-week-old Mc4r-KO F/F and Mc4r-KO HKO mice maintained on an NCD. All images are representative of 5 mice per group. Scale bars, 100 μm (D). (F and G) Plasma transaminase levels (n = 5) (F) as well as RT-qPCR analysis of hepatic gene expression related to ER stress, inflammation, or apoptosis (n = 5) (G) for 16- to 20-week-old fed mice of the indicated genotypes maintained on an NCD. (H and I) Blood glucose (n = 7) (H) and plasma insulin (n = 6) (I) levels in the fasted and fed states for mice at 16 to 18 weeks of age. (J and K) An ITT (2 U of human regular insulin per kg of BW) (n = 8) (J) and IPGTT (1.5 g of glucose per kg of BW) (n = 7) (K) for 16- to 19-week-old mice. (L) Immunoblot analysis of lipogenic enzymes in the fed liver of 10-week-old ob/ob F/F and ob/ob HKO mice as well as 16- to 18-week-old Mc4r-KO F/F and Mc4r-KO HKO mice maintained on an NCD. (M) Hepatic abundance of newly synthesized palmitate in the fasted state (6 hours) for 10-week-old F/F, HKO, ob/ob F/F, and ob/ob HKO mice and for 16- to 18-week-old Mc4r-KO F/F and Mc4r-KO HKO mice maintained on an NCD (n = 5). All quantitative data are means + SEM for the indicated numbers of mice. *P < 0.05, **P < 0.01 compared with Mc4r-KO F/F mice or as indicated (2-tailed Student’s t test [C, E, H, I, and K] or 1-way ANOVA followed by Bonferroni’s multiple-comparison test [F, G, and M]).