Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

Study Overview
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Brief Summary
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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.

Official Title
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Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia

Conditions
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Non-alcoholic Fatty Liver, Atherogenic Dyslipidemia, Insulin Resistance

Intervention / Treatment
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* Diagnostic Test: Lipoprotein kinetics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ApoC-III LOF<br>Carriers of apo-CIII loss-of-function mutation | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| ApoC-III GOF<br>Carriers of apo-CIII gain-of-function mutation | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| TM6SF2-KK<br>Carriers of TM6SF2 E167K mutation | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| PNLPLA3-MM<br>Carriers of PNLPLA3 I148M mutation | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| Control<br>No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| ApoE variants<br>Carriers of E2/2, E3/3 or E4/4 mutation | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| LIPG<br>LIPG gene LOF or GOF variant carriers | Diagnostic Test: Lipoprotein kinetics<br>* Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.<br>* Other names: Measurement of liver fat;|
| ANGPTL3 or ANGPTL8<br>ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the rate of production of VLDL Apo B | Production rate, mg/day | Baseline | 
| Difference in the rate of production of VLDL Triglycerides | Production rate, mg/kg/day | Baseline | 
| Difference in the rate of production of VLDL ApoC-III and apoE | Production rate, mg/kg/day | Baseline | 
| Difference in the Fractional Catabolic Rate of VLDL Apo B | Rate of disappearance, pools/day | Baseline | 
| Difference in the Fractional Catabolic Rate of VLDL Triglycerides | Rate of disappearance, pools/day | Baseline | 
| Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE | Rate of disappearance, pools/day | Baseline | 
| Difference in de novo lipogenesis | Measure of newly synthesized triglycerides in VLDL, μmol/l | Baseline | 
| Difference in liver fat | Percentage of liver fat measured with magnetic resonance spectroscopy | Baseline | 
| Difference in atherogenic dyslipidemia | Remnant lipoproteins and lipoprotein fraction composition, mg/L | Baseline | 
| Difference in insulin resistance | Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | Baseline | 
| Difference in apoprotein A concentration | ApoA, mg/dl | Baseline | 
| Difference in apoprotein B concentration | ApoB, mg/dl | Baseline | 
| Difference in apoprotein C concentration | ApoC, mg/dl | Baseline | 
| Difference in apoprotein E concentration | ApoE, mg/dl | Baseline | 
| Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B | Rate of turnover, pools/day | Baseline | 
| Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B | Rate of turnover, pools/day | Baseline | 
| Lipolytic activity | Measured lipoprotein lipase activity, mU/ml | Baseline | 
| Hepatic lipase activity | Measured hepatic lipase activity, mU/ml | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-alcoholic Fatty Liver, Apoproteins, Genetic variants