Young Martin E, Guthrie Patrick H, Razeghi Peter, Leighton Brendan, Abbasi Shahrzad, Patil Sarita, Youker Keith A, Taegtmeyer Heinrich
Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, Houston, Texas 77030, USA.
Diabetes. 2002 Aug;51(8):2587-95. doi: 10.2337/diabetes.51.8.2587.
We investigated whether decreased responsiveness of the heart to physiological increases in fatty acid availability results in lipid accumulation and lipotoxic heart disease. Lean and obese Zucker rats were either fed ad libitum or fasted overnight. Fasting increased plasma nonesterified fatty acid levels in both lean and obese rats, although levels were greatest in obese rats regardless of nutritional status. Despite increased fatty acid availability, the mRNA transcript levels of peroxisome proliferator-activated receptor (PPAR)-alpha-regulated genes were similar in fed lean and fed obese rat hearts. Fasting increased expression of all PPAR-alpha -regulated genes in lean Zucker rat hearts, whereas, in obese Zucker rat hearts, muscle carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase were unaltered with fasting. Rates of oleate oxidation were similar for hearts from fed rats. However, fasting increased rates of oleate oxidation only in hearts from lean rats. Dramatic lipid deposition occurred within cardiomyocytes of obese, but not lean, Zucker rats upon fasting. Cardiac output was significantly depressed in hearts isolated from obese rats compared with lean rats, regardless of nutritional status. Fasting increased cardiac output in hearts of lean rats only. Thus, the heart's inability to increase fatty acid oxidation in proportion to increased fatty acid availability is associated with lipid accumulation and contractile dysfunction of the obese Zucker rat.
我们研究了心脏对生理水平脂肪酸可用性增加的反应性降低是否会导致脂质蓄积和脂毒性心脏病。将瘦型和肥胖型Zucker大鼠随意喂食或禁食过夜。禁食使瘦型和肥胖型大鼠的血浆非酯化脂肪酸水平均升高，尽管无论营养状况如何，肥胖型大鼠的水平最高。尽管脂肪酸可用性增加，但在喂食的瘦型和肥胖型大鼠心脏中，过氧化物酶体增殖物激活受体（PPAR）-α调控基因的mRNA转录水平相似。禁食增加了瘦型Zucker大鼠心脏中所有PPAR-α调控基因的表达，而在肥胖型Zucker大鼠心脏中，肌肉肉碱棕榈酰转移酶和中链酰基辅酶A脱氢酶在禁食后未发生改变。喂食大鼠心脏的油酸氧化速率相似。然而，禁食仅增加了瘦型大鼠心脏的油酸氧化速率。禁食后，肥胖型Zucker大鼠的心肌细胞内发生了显著的脂质沉积，而瘦型大鼠则没有。无论营养状况如何，与瘦型大鼠相比，从肥胖型大鼠分离的心脏的心输出量显著降低。禁食仅增加了瘦型大鼠心脏的心输出量。因此，心脏无法随着脂肪酸可用性的增加而相应增加脂肪酸氧化，这与肥胖型Zucker大鼠的脂质蓄积和收缩功能障碍有关。
