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 5

Hepatic glycogen accumulation and suppression of glycolysis coordinately exacerbate fed hyperglycemia in ob/ob HKO mice.

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Hepatic glycogen accumulation and suppression of glycolysis coordinately...
(A) Metabolomic profiling of the liver of NCD-fed ob/ob F/F and ob/ob HKO mice in the fed state at 10 weeks of age (n = 3 to 6). Liver metabolites were measured by mass spectrometry. Results are depicted as a pathway activity map; red and blue indicate metabolites with an increased or decreased abundance, respectively, in ob/ob HKO mice compared with ob/ob F/F mice. Metabolites in parentheses were not detected. Quantitative data are provided in Supplemental Table 2. GK, glucokinase; PFK, phosphofructokinase; PPP, pentose phosphate pathway; HBP, hexosamine biosynthesis pathway; PK, pyruvate kinase. (B) Blood glucose concentrations at the indicated times during refeeding after food deprivation for 16 hours in 10- to 12-week-old ob/ob F/F and ob/ob HKO mice (n = 10). (C) Hepatic glycogen content in fasted (16 hours), refed (6 hours), and fed states for 10- to 12-week-old ob/ob F/F and ob/ob HKO mice (n = 5). (D) RT-qPCR analysis of Gys2 mRNA in the liver of fasted 10-week-old ob/ob HKO mice injected with an adenovirus encoding GS or a control virus (n = 3). (E) PAS staining of liver sections from 10-week-old ob/ob HKO mice in the fed or overnight-fasted state after injection with control or GS adenoviruses. Images are representative of 4 mice per condition. Scale bars, 200 μm. (F) Hepatic glycogen content in ob/ob HKO mice (n = 6) as in E. (G) An IPGTT (2 g of glucose per kg of BW) in ob/ob HKO mice injected with control or GS adenoviruses (n = 6). (H) Activity and mRNA abundance for liver-type PFK (encoded by Pfkl) in the liver of 10-week-old ob/ob F/F and ob/ob HKO mice in the fed state (n = 6). All quantitative data are means + SEM for the indicated numbers of mice. *P < 0.05, **P < 0.01 compared with ob/ob F/F mice or the control adenovirus, or as indicated (2-tailed Student’s t test in B–D, G, and H or 1-way ANOVA followed by Tukey’s multiple-comparison test in F).