Atherogenic Dyslipidemia, Insulin Resistance, Non-alcoholic Fatty Liver
Conditions
Keywords
Non-alcoholic Fatty Liver, Apoproteins, Genetic variants
Brief summary
The aims of the study are: 1. 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. 2. 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. 3. 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. 4. 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.
Interventions
DIAGNOSTIC_TESTLipoprotein kinetics
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.
Sponsors
Göteborg University
Marja-Riitta Taskinen
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in the rate of production of VLDL Apo B | Baseline | Production rate, mg/day |
| Difference in the rate of production of VLDL Triglycerides | Baseline | Production rate, mg/kg/day |
| Difference in the rate of production of VLDL ApoC-III and apoE | Baseline | Production rate, mg/kg/day |
| Difference in the Fractional Catabolic Rate of VLDL Apo B | Baseline | Rate of disappearance, pools/day |
| Difference in the Fractional Catabolic Rate of VLDL Triglycerides | Baseline | Rate of disappearance, pools/day |
| Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE | Baseline | Rate of disappearance, pools/day |
| Difference in de novo lipogenesis | Baseline | Measure of newly synthesized triglycerides in VLDL, μmol/l |
| Difference in liver fat | Baseline | Percentage of liver fat measured with magnetic resonance spectroscopy |
| Difference in atherogenic dyslipidemia | Baseline | Remnant lipoproteins and lipoprotein fraction composition, mg/L |
| Difference in insulin resistance | Baseline | Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) |
| Difference in apoprotein A concentration | Baseline | ApoA, mg/dl |
| Difference in apoprotein B concentration | Baseline | ApoB, mg/dl |
| Difference in apoprotein C concentration | Baseline | ApoC, mg/dl |
| Difference in apoprotein E concentration | Baseline | ApoE, mg/dl |
| Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B | Baseline | Rate of turnover, pools/day |
| Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B | Baseline | Rate of turnover, pools/day |
| Lipolytic activity | Baseline | Measured lipoprotein lipase activity, mU/ml |
| Hepatic lipase activity | Baseline | Measured hepatic lipase activity, mU/ml |
Countries
Finland, Sweden
Outcome results
None listed