Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 100
- 试验地点
- 2
- 主要终点
- Difference in de novo lipogenesis
研究概览
简要总结
The aims of the study are:
- To investigate if carriers of apolipoprotein (apo) CIII loss-of-function (LOF) mutations produce less apo-CIII that results in reduction of large very low-density lipoprotein (VLDL) particle secretion as compared to non-carriers of these variants and compare the results with carriers of apo-CIII gain-of-function (GOF) to elucidate the role of apo-CIII in hepatic lipid metabolism.
- To study if carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations produce less large VLDL particles to transport fat out of the liver as compared to non-carriers.
- To test whether the specific mutations in the apo-CIII, TM6SF2 and PNLPLA3 genes are reflected in changes of liver de novo lipogenesis (DNL), liver fat, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), plasma lipid and apolipoprotein kinetics and fasting concentrations in carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations as compared to non-carriers.
- To study the effects of APOE, angiopoietin (ANGPTL3 and ANGPTL8) or endothelial lipase (LIPG) genotypes on liver fat metabolism, lipid and apolipoprotein metabolism and lipid phenotypes.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •persons who have provided written consent
- •apo-CIII loss-of-function mutation (heterozygous) or apo-CIII gain-of-function mutations (heterozygous) or TM6SF2 E167K mutation (homozygous) or PNLPLA3 I148M or apoE or LIPG or ANGPTL3 or ANGPTL8 LOF and GOF variants. Control group without any of known risk variants in these genes.
- •Hemoglobin A1c < 6.5%
- •Body mass index between 18.5 and 40 kg/m²
- •Estimated glomerular filtration rate > 60 ml/min/1.73 m² at inclusion
排除标准
- •Patients with Type 1 and 2 diabetes, BMI > 40 kg/m2,
- •ApoE2/2 phenotype, thyrotropin concentration outside normal range,
- •Lipid-lowering drugs
- •Blood pressure >160 mmHg systolic and/or > 105 diastolic mmHg
- •Liver failure or abnormal liver function tests >3 x upper limit of normal
- •Intestinal disease
- •Pregnancy, breastfeeding
- •Patients with volume depletion
结局指标
主要结局
Difference in de novo lipogenesis
时间窗: Baseline
Measure of newly synthesized triglycerides in VLDL, μmol/l
Difference in the rate of production of VLDL ApoC-III and apoE
时间窗: Baseline
Production rate, mg/kg/day
Difference in the rate of production of VLDL Apo B
时间窗: Baseline
Production rate, mg/day
Difference in the rate of production of VLDL Triglycerides
时间窗: Baseline
Production rate, mg/kg/day
Difference in apoprotein E concentration
时间窗: Baseline
ApoE, mg/dl
Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
时间窗: Baseline
Rate of turnover, pools/day
Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
时间窗: Baseline
Rate of turnover, pools/day
Difference in the Fractional Catabolic Rate of VLDL Apo B
时间窗: Baseline
Rate of disappearance, pools/day
Difference in the Fractional Catabolic Rate of VLDL Triglycerides
时间窗: Baseline
Rate of disappearance, pools/day
Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
时间窗: Baseline
Rate of disappearance, pools/day
Difference in apoprotein C concentration
时间窗: Baseline
ApoC, mg/dl
Difference in liver fat
时间窗: Baseline
Percentage of liver fat measured with magnetic resonance spectroscopy
Lipolytic activity
时间窗: Baseline
Measured lipoprotein lipase activity, mU/ml
Hepatic lipase activity
时间窗: Baseline
Measured hepatic lipase activity, mU/ml
Difference in atherogenic dyslipidemia
时间窗: Baseline
Remnant lipoproteins and lipoprotein fraction composition, mg/L
Difference in insulin resistance
时间窗: Baseline
Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Difference in apoprotein A concentration
时间窗: Baseline
ApoA, mg/dl
Difference in apoprotein B concentration
时间窗: Baseline
ApoB, mg/dl
次要结局
未报告次要终点
研究者
Marja-Riitta Taskinen
Professor
Helsinki University Central Hospital