Kasuga M

References (4)

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

Title : Diet-induced up-regulation of gene expression in adipocytes without changes in DNA methylation - Okada_2009_Kobe.J.Med.Sci_54_E241
Author(s) : Okada Y , Sakaue H , Nagare T , Kasuga M
Ref : Kobe J Med Sci , 54 :E241 , 2009
Abstract : The expansion of white adipose tissue (WAT) mass during the development of obesity is mediated in part through an increase in adipocyte size. Although gene expression profiles associated with adipogenesis in vitro and the development of obesity in vivo have been characterized by DNA microarray analysis, the role of chromatin and chromatin-modifying proteins in the regulation of gene expression related to adipocyte hypertrophy has remained unclear. We have now shown that maintenance of C57BL/6J mice on a high-fat diet for 16 weeks resulted in marked up-regulation of the expression of leptin, Mest (mesoderm specific transcript; also known as paternally expressed gene 1, or Peg1), and sFRP5 (secreted frizzled-related protein 5) genes in WAT. Furthermore, the demethylating agent 5-aza-2'-deoxycytidine increased the amount of Mest/Peg1 mRNA, but not that of leptin or sFRP5 mRNAs, in mouse 3T3-L1 adipocytes. However, analysis by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry revealed that maintenance of mice on a high-fat diet for various times did not affect the level of methylation at specific CpG sites in the promoter regions of leptin, Mest/Peg1, and sFRP5 genes in WAT. Our results indicate that the diet-induced up-regulation of leptin, Mest/Peg1, and sFRP5 gene expression in WAT during the development of obesity in mice is not mediated directly by changes in DNA methylation.
ESTHER : Okada_2009_Kobe.J.Med.Sci_54_E241
PubMedSearch : Okada_2009_Kobe.J.Med.Sci_54_E241
PubMedID: 19628964

Title : Cloning of rabbit LCAT cDNA: increase in LCAT mRNA abundance in the liver of cholesterol-fed rabbits - Murata_1996_J.Lipid.Res_37_1616
Author(s) : Murata Y , Maeda E , Yoshino G , Kasuga M
Ref : J Lipid Res , 37 :1616 , 1996
Abstract : Structure of rabbit lecithin:cholesterol acyltransferase (LCAT) and molecular basis for the effects of cholesterol feeding on LCAT expression were investigated by cloning and sequencing LCAT cDNA from rabbit. The rabbit and human sequences are 91% identical at the nucleotide level and 93% identical at the amino acid level. The interfacial substrate active site, asparagine-linked glycosylation sites, and sites at which rare mutations cause human familial LCAT deficiency are all highly conserved in the rabbit protein. The apparent molecular mass of rabbit LCAT, as determined by immunoblot analysis, was approximately equal to that of human LCAT. Rabbits showed 2.6- and 5.5-fold increases in serum LCAT activity 3 and 6 weeks, respectively, after switching to a cholesterol-enriched diet. Northern blot analysis revealed that the abundance of LCAT mRNA in liver increased 1.6- and 2.8-fold after 3 and 6 weeks, respectively, of cholesterol feeding. The marked temporal relation between the increase in serum LCAT activity and the liver LCAT mRNA abundance suggest that the regulation of LCAT activity in vivo may be primarily determined by changes in the amount of LCAT mRNA.
ESTHER : Murata_1996_J.Lipid.Res_37_1616
PubMedSearch : Murata_1996_J.Lipid.Res_37_1616
PubMedID: 8827532
Gene_locus related to this paper: rabit-lcat

Title : Lecithin-cholesterol acyltransferase (LCAT) deficiency with a missense mutation in exon 6 of the LCAT gene - Maeda_1991_Biochem.Biophys.Res.Commun_178_460
Author(s) : Maeda E , Naka Y , Matozaki T , Sakuma M , Akanuma Y , Yoshino G , Kasuga M
Ref : Biochemical & Biophysical Research Communications , 178 :460 , 1991
Abstract : The plasma enzyme, human lecithin-cholesterol acyltransferase (LCAT) is responsible for the majority of cholesterol ester formation in human plasma and is a key enzyme of the reverse transport of cholesterol from peripheral tissue to the liver. We sequenced genomic DNA of the LCAT gene from a Japanese male patient who was clinically and biochemically diagnosed as a familial LCAT deficiency. Analysis of all exons and exon-intron boundaries revealed only a single G to A transition within the sixth exon of both allele of the gene, leading to the substitution of methionine for isoleucinle at residue 293 of the mature enzyme. This mutation creates a new hexanucleotide recognition site for the restriction endonuclease Ndel. Familial study of Ndel digestion of the genomic DNA and determination of plasma LCAT activity established that the patient and his sister whose plasma LCAT activity were extremely reduced were homozygous and his children whose plasma LCAT activity were about half of normal controls were heterozygous for this mutation.
ESTHER : Maeda_1991_Biochem.Biophys.Res.Commun_178_460
PubMedSearch : Maeda_1991_Biochem.Biophys.Res.Commun_178_460
PubMedID: 1859405
Gene_locus related to this paper: human-LCAT