Yahagi N

References (10)

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 : Role of Hormone-sensitive Lipase in Leptin-Promoted Fat Loss and Glucose Lowering - Takanashi_2017_J.Atheroscler.Thromb_24_1105
Author(s) : Takanashi M , Taira Y , Okazaki S , Takase S , Kimura T , Li CC , Xu PF , Noda A , Sakata I , Kumagai H , Ikeda Y , Iizuka Y , Yahagi N , Shimano H , Osuga JI , Ishibashi S , Kadowaki T , Okazaki H
Ref : J Atheroscler Thromb , 24 :1105 , 2017
Abstract : AIM: Myriad biological effects of leptin may lead to broad therapeutic applications for various metabolic diseases, including diabetes and its complications; however, in contrast to its anorexic effect, the molecular mechanisms underlying adipopenic and glucose-lowering effects of leptin have not been fully understood. Here we aim to clarify the role of hormone-sensitive lipase (HSL) in leptin's action. METHODS: Wild-type (WT) and HSL-deficient (HSLKO) mice were made hyperleptinemic by two commonly-used methods: adenovirus-mediated overexpression of leptin and continuous subcutaneous infusion of leptin by osmotic pumps. The amount of food intake, body weights, organ weights, and parameters of glucose and lipid metabolism were measured. RESULTS: Hyperleptinemia equally suppressed the food intake in WT and HSLKO mice. On the other hand, leptin-mediated fat loss and glucose-lowering were significantly blunted in the absence of HSL when leptin was overexpressed by recombinant adenovirus carrying leptin. By osmotic pumps, the fat-losing and glucose-lowering effects of leptin were milder due to lower levels of hyperleptinemia; although the difference between WT and HSLKO mice did not reach statistical significance, HSLKO mice had a tendency to retain more fat than WT mice in the face of hyperleptinemia. CONCLUSIONS: We clarify for the first time the role of HSL in leptin's effect using a genetic model: leptin-promoted fat loss and glucose-lowering are at least in part mediated via HSL-mediated lipolysis. Further studies to define the pathophysiological role of adipocyte lipases in leptin action may lead to a new therapeutic approach to circumvent leptin resistance.
ESTHER : Takanashi_2017_J.Atheroscler.Thromb_24_1105
PubMedSearch : Takanashi_2017_J.Atheroscler.Thromb_24_1105
PubMedID: 28413180

Title : Abrogation of neutral cholesterol ester hydrolytic activity causes adrenal enlargement - Ohta_2011_Biochem.Biophys.Res.Commun_404_254
Author(s) : Ohta K , Sekiya M , Uozaki H , Igarashi M , Takase S , Kumagai M , Takanashi M , Takeuchi Y , Izumida Y , Kubota M , Nishi M , Okazaki H , Iizuka Y , Yahagi N , Yagyu H , Fukayama M , Kadowaki T , Ohashi K , Ishibashi S , Osuga J
Ref : Biochemical & Biophysical Research Communications , 404 :254 , 2011
Abstract : We have previously demonstrated that neutral cholesterol ester hydrolase 1 (Nceh1) regulates foam cell formation and atherogenesis through the catalytic activity of cholesterol ester hydrolysis, and that Nceh1 and hormone-sensitive lipase (Lipe) are responsible for the majority of neutral cholesterol ester hydrolase activity in macrophages. There are several cholesterol ester-metabolizing tissues and cells other than macrophages, among which adrenocortical cells are also known to utilize the intracellular cholesterol for steroidogenesis. It has been believed that the mobilization of intracellular cholesterol ester in adrenal glands was facilitated solely by Lipe. We herein demonstrate that Nceh1 is also involved in cholesterol ester hydrolysis in adrenal glands. While Lipe deficiency remarkably reduced the neutral cholesterol ester hydrolase activity in adrenal glands as previously reported, additional inactivation of Nceh1 gene completely abrogated the activity. Adrenal glands were enlarged in proportion to the degree of reduced neutral cholesterol ester hydrolase activity, and the enlargement of adrenal glands and the accumulation of cholesterol esters were most pronounced in the Nceh1/Lipe double-deficient mice. Thus Nceh1 is involved in the adrenal cholesterol metabolism, and the cholesterol ester hydrolytic activity in adrenal glands is associated with the organ enlargement.
ESTHER : Ohta_2011_Biochem.Biophys.Res.Commun_404_254
PubMedSearch : Ohta_2011_Biochem.Biophys.Res.Commun_404_254
PubMedID: 21111707
Gene_locus related to this paper: human-LIPE , human-NCEH1

Title : Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis - Sekiya_2009_Cell.Metab_10_219
Author(s) : Sekiya M , Osuga J , Nagashima S , Ohshiro T , Igarashi M , Okazaki H , Takahashi M , Tazoe F , Wada T , Ohta K , Takanashi M , Kumagai M , Nishi M , Takase S , Yahagi N , Yagyu H , Ohashi K , Nagai R , Kadowaki T , Furukawa Y , Ishibashi S
Ref : Cell Metab , 10 :219 , 2009
Abstract : Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1(Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes foam cell formation and the development of atherosclerosis in mice. We further demonstrate that Nceh1 and Lipe mediate a comparable degree of nCEH activity in macrophages and together account for most of the activity. Mice lacking both Nceh1 and Lipe aggravated atherosclerosis in an additive manner. Thus, Nceh1 is a promising target for the treatment of atherosclerosis.
ESTHER : Sekiya_2009_Cell.Metab_10_219
PubMedSearch : Sekiya_2009_Cell.Metab_10_219
PubMedID: 19723498
Gene_locus related to this paper: human-NCEH1 , mouse-Q8BLF1

Title : Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages - Okazaki_2008_J.Biol.Chem_283_33357
Author(s) : Okazaki H , Igarashi M , Nishi M , Sekiya M , Tajima M , Takase S , Takanashi M , Ohta K , Tamura Y , Okazaki S , Yahagi N , Ohashi K , Amemiya-Kudo M , Nakagawa Y , Nagai R , Kadowaki T , Osuga J , Ishibashi S
Ref : Journal of Biological Chemistry , 283 :33357 , 2008
Abstract : Unstable lipid-rich plaques in atherosclerosis are characterized by the accumulation of macrophage foam cells loaded with cholesterol ester (CE). Although hormone-sensitive lipase and cholesteryl ester hydrolase (CEH) have been proposed to mediate the hydrolysis of CE in macrophages, circumstantial evidence suggests the presence of other enzymes with neutral cholesterol ester hydrolase (nCEH) activity. Here we show that the murine orthologue of KIAA1363, designated as neutral cholesterol ester hydrolase (NCEH), is a microsomal nCEH with high expression in murine and human macrophages. The effect of various concentrations of NaCl on its nCEH activity resembles that on endogenous nCEH activity of macrophages. RNA silencing of NCEH decreases nCEH activity at least by 50%; conversely, its overexpression inhibits the CE formation in macrophages. Immunohistochemistry reveals that NCEH is expressed in macrophage foam cells in atherosclerotic lesions. These data indicate that NCEH is responsible for a major part of nCEH activity in macrophages and may be a potential therapeutic target for the prevention of atherosclerosis.
ESTHER : Okazaki_2008_J.Biol.Chem_283_33357
PubMedSearch : Okazaki_2008_J.Biol.Chem_283_33357
PubMedID: 18782767
Gene_locus related to this paper: human-NCEH1

Title : Hormone-sensitive lipase is involved in hepatic cholesteryl ester hydrolysis - Sekiya_2008_J.Lipid.Res_49_1829
Author(s) : Sekiya M , Osuga J , Yahagi N , Okazaki H , Tamura Y , Igarashi M , Takase S , Harada K , Okazaki S , Iizuka Y , Ohashi K , Yagyu H , Okazaki M , Gotoda T , Nagai R , Kadowaki T , Shimano H , Yamada N , Ishibashi S
Ref : J Lipid Res , 49 :1829 , 2008
Abstract : Hormone-sensitive lipase (HSL) regulates the hydrolysis of acylglycerol and cholesteryl ester (CE) in various organs, including adipose tissues. However, the hepatic expression level of HSL has been reported to be almost negligible. In the present study, we found that mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) showed massive accumulation of CE in the liver compared with Lep(ob/ob)/HSL(+/+) mice, while triacylglycerol (TG) accumulation was modest. Similarly, feeding with a high-cholesterol diet induced hepatic CE accumulation in HSL(-/-) mice. Supporting these observations, we detected significant expression of protein as well as mRNA of HSL in the liver. HSL(-/-) mice showed reduced activity of CE hydrolase, but not of TG lipase, in the liver compared with wild-type mice. Furthermore, we confirmed the expression of HSL in viable parenchymal cells isolated from wild-type mice. The hepatocytes from HSL(-/-) mice showed reduced activity of CE hydrolase and contained more CE than those from HSL(+/+) mice even without the incubation with lipoproteins. Incubation with LDL further augmented the accumulation of CE in the HSL-deficient hepatocytes. From these results, we conclude that HSL is involved in the hydrolysis of CE in hepatocyes.
ESTHER : Sekiya_2008_J.Lipid.Res_49_1829
PubMedSearch : Sekiya_2008_J.Lipid.Res_49_1829
PubMedID: 18480494

Title : Identification of a novel member of the carboxylesterase family that hydrolyzes triacylglycerol: a potential role in adipocyte lipolysis - Okazaki_2006_Diabetes_55_2091
Author(s) : Okazaki H , Igarashi M , Nishi M , Tajima M , Sekiya M , Okazaki S , Yahagi N , Ohashi K , Tsukamoto K , Amemiya-Kudo M , Matsuzaka T , Shimano H , Yamada N , Aoki J , Morikawa R , Takanezawa Y , Arai H , Nagai R , Kadowaki T , Osuga J , Ishibashi S
Ref : Diabetes , 55 :2091 , 2006
Abstract : Molecular mechanisms underlying lipolysis, as defined by mobilization of fatty acids from adipose tissue, are not fully understood. A database search for enzymes with alpha/beta hydrolase folds, the GXSXG motif for serine esterase and the His-Gly dipeptide motif, has provided a previously unannotated gene that is induced during 3T3-L1 adipocytic differentiation. Because of its remarkable structural resemblance to triacylglycerol hydrolase (TGH) with 70.4% identity, we have tentatively designated this enzyme as TGH-2 and the original TGH as TGH-1. TGH-2 is also similar to TGH-1 in terms of tissue distribution, subcellular localization, substrate specificity, and regulation. Both enzymes are predominantly expressed in liver, adipose tissue, and kidney. In adipocytes, they are localized in microsome and fatcake. Both enzymes hydrolyzed p-nitophenyl butyrate, triolein, and monoolein but not diolein, cholesteryl oleate, or phospholipids; hydrolysis of short-chain fatty acid ester was 30,000-fold more efficient than that of long-chain fatty acid triacylglycerol. Fasting increased the expression of both genes in white adipose tissue, whereas refeeding suppressed their expression. RNA silencing of TGH-2 reduced isoproterenol-stimulated glycerol release by 10% in 3T3-L1 adipocytes, while its overexpression increased the glycerol release by 20%. Thus, TGH-2 may make a contribution to adipocyte lipolysis during period of increased energy demand.
ESTHER : Okazaki_2006_Diabetes_55_2091
PubMedSearch : Okazaki_2006_Diabetes_55_2091
PubMedID: 16804080

Title : Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob\/ob mice - Sekiya_2004_J.Biol.Chem_279_15084
Author(s) : Sekiya M , Osuga J , Okazaki H , Yahagi N , Harada K , Shen WJ , Tamura Y , Tomita S , Iizuka Y , Ohashi K , Okazaki M , Sata M , Nagai R , Fujita T , Shimano H , Kraemer FB , Yamada N , Ishibashi S
Ref : Journal of Biological Chemistry , 279 :15084 , 2004
Abstract : Hormone-sensitive lipase (HSL) plays a crucial role in the hydrolysis of triacylglycerol and cholesteryl ester in various tissues including adipose tissues. To explore the role of HSL in the metabolism of fat and carbohydrate, we have generated mice lacking both leptin and HSL (Lep(ob/ob)/HSL(-/-)) by cross-breeding HSL(-/-) mice with genetically obese Lep(ob/ob) mice. Unexpectedly, Lep(ob/ob)/HSL(-/-) mice ate less food, gained less weight, and had lower adiposity than Lep(ob/ob)/HSL(+/+) mice. Lep(ob/ob)/HSL(-/-) mice had massive accumulation of preadipocytes in white adipose tissues with increased expression of preadipocyte-specific genes (CAAT/enhancer-binding protein beta and adipose differentiation-related protein) and decreased expression of genes characteristic of mature adipocytes (CCAAT/enhancer-binding protein alpha, peroxisome proliferator activator receptor gamma, and adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1). Consistent with the reduced food intake, hypothalamic expression of neuropeptide Y and agouti-related peptide was decreased. Since HSL is expressed in hypothalamus, we speculate that defective generation of free fatty acids in the hypothalamus due to the absence of HSL mediates the altered expression of these orexigenic neuropeptides. Thus, deficiency of both leptin and HSL has unmasked novel roles of HSL in adipogenesis as well as in feeding behavior.
ESTHER : Sekiya_2004_J.Biol.Chem_279_15084
PubMedSearch : Sekiya_2004_J.Biol.Chem_279_15084
PubMedID: 14752112

Title : Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)\/Lep(ob) mice - Yahagi_2002_J.Biol.Chem_277_19353
Author(s) : Yahagi N , Shimano H , Hasty AH , Matsuzaka T , Ide T , Yoshikawa T , Amemiya-Kudo M , Tomita S , Okazaki H , Tamura Y , Iizuka Y , Ohashi K , Osuga J , Harada K , Gotoda T , Nagai R , Ishibashi S , Yamada N
Ref : Journal of Biological Chemistry , 277 :19353 , 2002
Abstract : Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficient Lep(ob)/Lep(ob) mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep(ob/ob) x Srebp-1(-/-) mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice.
ESTHER : Yahagi_2002_J.Biol.Chem_277_19353
PubMedSearch : Yahagi_2002_J.Biol.Chem_277_19353
PubMedID: 11923308

Title : Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity - Osuga_2000_Proc.Natl.Acad.Sci.U.S.A_97_787
Author(s) : Osuga J , Ishibashi S , Oka T , Yagyu H , Tozawa R , Fujimoto A , Shionoiri F , Yahagi N , Kraemer FB , Tsutsumi O , Yamada N
Ref : Proc Natl Acad Sci U S A , 97 :787 , 2000
Abstract : Hormone-sensitive lipase (HSL) is known to mediate the hydrolysis not only of triacylglycerol stored in adipose tissue but also of cholesterol esters in the adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the development of obesity and steroidogenesis, we generated HSL knockout mice by homologous recombination in embryonic stem cells. Mice homozygous for the mutant HSL allele (HSL-/-) were superficially normal except that the males were sterile because of oligospermia. HSL-/- mice did not have hypogonadism or adrenal insufficiency. Instead, the testes completely lacked neutral cholesterol ester hydrolase (NCEH) activities and contained increased amounts of cholesterol ester. Many epithelial cells in the seminiferous tubules were vacuolated. NCEH activities were completely absent from both brown adipose tissue (BAT) and white adipose tissue (WAT) in HSL-/- mice. Consistently, adipocytes were significantly enlarged in the BAT (5-fold) and, to a lesser extent in the WAT (2-fold), supporting the concept that the hydrolysis of triacylglycerol was, at least in part, impaired in HSL-/- mice. The BAT mass was increased by 1.65-fold, but the WAT mass remained unchanged. Discrepancy of the size differences between cell and tissue suggests the heterogeneity of adipocytes. Despite these morphological changes, HSL-/- mice were neither obese nor cold sensitive. Furthermore, WAT from HSL-/- mice retained 40% of triacylglycerol lipase activities compared with the wild-type WAT. In conclusion, HSL is required for spermatogenesis but is not the only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.
ESTHER : Osuga_2000_Proc.Natl.Acad.Sci.U.S.A_97_787
PubMedSearch : Osuga_2000_Proc.Natl.Acad.Sci.U.S.A_97_787
PubMedID: 10639158
Gene_locus related to this paper: human-LIPE , mouse-hslip