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.
Study Type
OBSERVATIONAL
Enrollment
100
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.
RPU Clinical and Molecular Metabolism, Biomedicum
Helsinki, Finland
Wallenberg Laboratory
Gothenburg, Sweden
Difference in the rate of production of VLDL Apo B
Production rate, mg/day
Time frame: Baseline
Difference in the rate of production of VLDL Triglycerides
Production rate, mg/kg/day
Time frame: Baseline
Difference in the rate of production of VLDL ApoC-III and apoE
Production rate, mg/kg/day
Time frame: Baseline
Difference in the Fractional Catabolic Rate of VLDL Apo B
Rate of disappearance, pools/day
Time frame: Baseline
Difference in the Fractional Catabolic Rate of VLDL Triglycerides
Rate of disappearance, pools/day
Time frame: Baseline
Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
Rate of disappearance, pools/day
Time frame: Baseline
Difference in de novo lipogenesis
Measure of newly synthesized triglycerides in VLDL, μmol/l
Time frame: Baseline
Difference in liver fat
Percentage of liver fat measured with magnetic resonance spectroscopy
Time frame: Baseline
Difference in atherogenic dyslipidemia
Remnant lipoproteins and lipoprotein fraction composition, mg/L
Time frame: Baseline
Difference in insulin resistance
Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Time frame: Baseline
Difference in apoprotein A concentration
ApoA, mg/dl
Time frame: Baseline
Difference in apoprotein B concentration
ApoB, mg/dl
Time frame: Baseline
Difference in apoprotein C concentration
ApoC, mg/dl
Time frame: Baseline
Difference in apoprotein E concentration
ApoE, mg/dl
Time frame: Baseline
Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
Rate of turnover, pools/day
Time frame: Baseline
Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
Rate of turnover, pools/day
Time frame: Baseline
Lipolytic activity
Measured lipoprotein lipase activity, mU/ml
Time frame: Baseline
Hepatic lipase activity
Measured hepatic lipase activity, mU/ml
Time frame: Baseline
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