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 8

Proposed mechanisms by which hepatic FASN deficiency in NCD-fed ob/ob or Mc4r-KO mice affects NAFLD and diabetes.

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Proposed mechanisms by which hepatic FASN deficiency in NCD-fed ob/ob or...
(A) In the liver of fasted ob/ob HKO mice, FAO is impaired, which results in suppression of gluconeogenesis via AMPK-dependent and -independent mechanisms and thereby leads to fasting hypoglycemia. Gck expression is also upregulated by an unknown mechanism. Suppression of gluconeogenesis and upregulation of GK together promote HGU during an IPGTT, resulting in improved glucose tolerance. (B) In the liver of Mc4r-KO HKO mice, suppression of DNL alleviates hepatic steatosis. Gluconeogenesis is also suppressed as a result of inhibition of FAO and augmentation of insulin signaling. This suppression of gluconeogenesis and enhanced insulin signaling cooperatively improve glucose metabolism. (C) In the liver of fed ob/ob F/F mice, dietary glucose is metabolized predominantly via glycolysis, the TCA cycle, and DNL as a result of sufficient glycogen accumulation. (D) In the liver of ob/ob HKO mice, DNL and gluconeogenesis are suppressed, resulting in alleviation of hepatic steatosis and promotion of glucose uptake. In the early postprandial state, dietary glucose is therefore metabolized predominantly through glycolysis, the TCA cycle, and glycogenesis, resulting in maintenance of blood glucose levels similar to those of ob/ob F/F mice. (E) In the liver of ob/ob HKO mice in the late postprandial and fed states, glycolysis is inhibited through citrate-mediated suppression of PFK activity. This inhibition of glycolysis and hepatic glycogen accumulation cooperatively restrain glucose utilization and uptake, resulting in glucose spillover and consequent exacerbation of fed hyperglycemia.