Vaziri N D, Liang K
Irvine Medical Center, Division of Nephrology and Hypertension, University of California, 101 The City Drive, Bldg. 53, Rm. 125, Rt. 81, Orange, CA 92868, USA.
Am J Physiol Renal Physiol. 2004 Nov;287(5):F1038-43. doi: 10.1152/ajprenal.00150.2004. Epub 2004 Jul 27.
Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic cardiovascular disease and profound alteration of plasma lipid profile. Uremic dyslipidemia is marked by increased plasma concentration of ApoB-containing lipoproteins and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport. These abnormalities are, in part, due to acquired LCAT deficiency and upregulation of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of cholesterol, thereby promoting hepatic production of ApoB-containing lipoproteins and constraining HDL-mediated cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg.kg(-1).day(-1)) or placebo for 6 wk. Sham-operated rats served as controls. Key cholesterol-regulating enzymes, plasma lipids, and creatinine clearance were measured. The untreated CRF rats exhibited increased plasma low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol, unchanged plasma HDL cholesterol, elevated total cholesterol-to-HDL cholesterol ratio, reduced liver microsomal free cholesterol, and diminished creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2 mRNA, ACAT-2 protein and ACAT activity, and unchanged hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase. ACAT inhibitor raised plasma HDL cholesterol, lowered LDL and VLDL cholesterol, and normalized total cholesterol-to-HDL cholesterol ratio without changing total cholesterol concentration (hence, a shift from ApoB-containing lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore the efficacy of ACAT inhibition in humans with CRF.
慢性肾衰竭（CRF）与动脉粥样硬化性心血管疾病风险增加及血浆脂质谱的显著改变相关。尿毒症性血脂异常的特征是含载脂蛋白B（ApoB）的脂蛋白血浆浓度升高以及高密度脂蛋白（HDL）介导的胆固醇逆向转运受损。这些异常部分归因于获得性卵磷脂胆固醇酰基转移酶（LCAT）缺乏和肝脏酰基辅酶A：胆固醇酰基转移酶（ACAT）上调。ACAT催化胆固醇的细胞内酯化，从而促进肝脏产生含ApoB的脂蛋白，并限制外周组织中HDL介导的胆固醇摄取。鉴于上述考虑因素，我们检验了ACAT的药理学抑制作用可能改善CRF诱导的血脂异常这一假说。将5/6肾切除大鼠用ACAT抑制剂IC - 976（30 mg·kg⁻¹·d⁻¹）或安慰剂治疗6周。假手术大鼠作为对照。测定关键的胆固醇调节酶、血浆脂质和肌酐清除率。未经治疗的CRF大鼠表现出血浆低密度脂蛋白（LDL）和极低密度脂蛋白（VLDL）胆固醇升高、血浆HDL胆固醇不变、总胆固醇与HDL胆固醇比值升高、肝微粒体游离胆固醇降低以及肌酐清除率降低。这伴随着血浆LCAT降低、肝脏ACAT - 2 mRNA、ACAT - 2蛋白和ACAT活性增加，以及肝脏3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶和胆固醇7α - 羟化酶不变。ACAT抑制剂使血浆HDL胆固醇升高、LDL和VLDL胆固醇降低，并使总胆固醇与HDL胆固醇比值正常化，而总胆固醇浓度不变（因此，从含ApoB的脂蛋白向HDL转变）。这伴随着肝脏ACAT活性和血浆LCAT的正常化。总之，抑制ACAT可逆转CRF大鼠的LCAT缺乏并改善血浆HDL水平。未来需要开展研究以探索ACAT抑制作用对CRF患者的疗效。
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