Matsukawa_2023_JCI.Insight_8__e161282

Reference

Title : Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models - Matsukawa_2023_JCI.Insight_8__e161282
Author(s) : Matsukawa T , Yagi T , Uchida T , Sakai M , Mitsushima M , Naganuma T , Yano H , Inaba Y , Inoue H , Yanagida K , Uematsu M , Nakao K , Nakao H , Aiba A , Nagashima Y , Kubota T , Kubota N , Izumida Y , Yahagi N , Unoki-Kubota H , Kaburagi Y , Asahara SI , Kido Y , Shindou H , Itoh M , Ogawa Y , Minami S , Terauchi Y , Tobe K , Ueki K , Kasuga M , Matsumoto M
Ref : JCI Insight , 8 : , 2023
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.
ESTHER : Matsukawa_2023_JCI.Insight_8__e161282
PubMedSearch : Matsukawa_2023_JCI.Insight_8__e161282
PubMedID: 37681411
Gene_locus related to this paper: human-FASN , mouse-FASN

Related information

Gene_locus related to this paper: human-FASN , mouse-FASN

Citations formats

Matsukawa T, Yagi T, Uchida T, Sakai M, Mitsushima M, Naganuma T, Yano H, Inaba Y, Inoue H, Yanagida K, Uematsu M, Nakao K, Nakao H, Aiba A, Nagashima Y, Kubota T, Kubota N, Izumida Y, Yahagi N, Unoki-Kubota H, Kaburagi Y, Asahara SI, Kido Y, Shindou H, Itoh M, Ogawa Y, Minami S, Terauchi Y, Tobe K, Ueki K, Kasuga M, Matsumoto M (2023)
Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models
JCI Insight 8 :

Matsukawa T, Yagi T, Uchida T, Sakai M, Mitsushima M, Naganuma T, Yano H, Inaba Y, Inoue H, Yanagida K, Uematsu M, Nakao K, Nakao H, Aiba A, Nagashima Y, Kubota T, Kubota N, Izumida Y, Yahagi N, Unoki-Kubota H, Kaburagi Y, Asahara SI, Kido Y, Shindou H, Itoh M, Ogawa Y, Minami S, Terauchi Y, Tobe K, Ueki K, Kasuga M, Matsumoto M (2023)
JCI Insight 8 :