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Ch 9. Lipotoxicity 2004. 5. 18. 정혜승. Introduction Definition of lipotoxicity : excess TG in nonadipocytes(=steatosis) → adverse effects on function or.

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Presentation on theme: "Ch 9. Lipotoxicity 2004. 5. 18. 정혜승. Introduction Definition of lipotoxicity : excess TG in nonadipocytes(=steatosis) → adverse effects on function or."— Presentation transcript:

1 Ch 9. Lipotoxicity 2004. 5. 18. 정혜승

2 Introduction Definition of lipotoxicity : excess TG in nonadipocytes(=steatosis) → adverse effects on function or viability of the cells Adipocyte 의 존재 이유 ; capacity to store surplus calories for fasting periods → “transient obesity” 현대의 산업화 사회 : no famine → progressive and permanent obesity Obesity → FFA 증가 → nonadipocyte 는 이들의 유입을 막을 방법이 없으므로 일단 다 받은 후 TG 로 변환함 → toxic effect 는 unoxidized long-chain fatty acyl coenzymeA(CoA) ( 예,palmitoyl CoA) 에 의해 나타 남 (fig 9.2) Rodent 에서 관찰된 Lipid-induced tissue dysfunction 은 사람의 metabolic syndrome 의 한 원인으로 여겨짐

3 Secreted from adipocytes → body fat mass 와 비례 Downregulates lipogenic enzyme, upregulates enzymes of FA oxidation in nonadipocytes 결국 stored fat 의 4% 만이 nonadipocyte 에 간다. Fig 9.4 Insulin → glucose tolerance of liver, muscle.. Leptin → fat tolerance of liver, muscle, islet… “antisteatotic hormone” –nonadipose tissue 의 fat 이 증가되어 있는 congenital lipodystrophy 환자에 게 leptin 을 투여하면 ectopic fat 이 감소하면서 인슐린 저항성이 감소함 “protector” - Leptin

4 Syndromes of lipotoxicity (rodents) Lipodystrophic syndrome (adipocyte deficiency) → no leptin → severe steatosis (fig 9.6) Leptin deficiency (ob/ob mouse) Congenital leptin resistance (db/db mouse, fa/fa ZDF rat) Diet-induced steatosis –High fat diet → relative hypoleptinemia → ectopic fat 증가 → insulin resistance –ZDF rat Islet lipid content 증가 → beta cell hyperplasia → hyperinsulinemia → islet lipid content 더욱 증가 → GLUT2 의 감소와 lipoapoptosis of beta cell → no further compensation for insulin resistance → overt DM Parallel to human?

5 Lipoapoptotic pathway (fig 9.2) via NF  B via peroxynitrite serine-palmitoyl transferase Acyl CoA + Serine ZDF rat 의 islet 에서 증가되어 있음 → leptin receptor transfer 한 후 leptin 투여하면 발현 감소 Insulin resistance 야기

6 Diet-induced metabolic syndrome 의 기전 ( 가설 ) Failure of liporegulatory system –Relative hypoleptinemia Obesity → leptin 이 많이 분비되긴 해도 넘쳐나는 FA 를 다 산화시킬 만큼은 안됨 Leptin 생성 : visceral fat << SQ fat Leptin 치료에 반응 ? –Postreceptor leptin resistance SOCS-3 (suppressor of cytokine signaling 3) –Leptin receptor 의 critical tyrosyl residue 에 결합하여 STAT-3 의 인산화 를 억제함 → FA 산화 감소 Other candidate factors ; SH-P-2, PIAS-3

7 Prevention of lipoapoptosis of beta cell in vivo Reverse obesity Restriction of diet and increase of physical activity Antisteatotic agents –iNOS inhibitors : nicotinamide, aminoguanidine –TZD 기전 ? ; AMP kinase 의 활성화 AICAR (aminoimidazole-4-carboxamide-1  -riboside) –Metformin 기전 ? ; AMP kinase 의 활성화 Acetyl CoA carboxylase activity 감소 → malonyl CoA 감소 → FA 산화 증가


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