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Enrolling by invitation NCT04209816

Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

— Observational Non-alcoholic Fatty Liver Atherogenic Dyslipidemia Insulin Resistance

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An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: Lipoprotein kinetics.
Who it may be relevant to
Registry conditions: Non-alcoholic Fatty Liver, Atherogenic Dyslipidemia, Insulin Resistance. Basic parameters: 18 years — 70 years · All.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
Finland, Sweden
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

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Official title

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

Overview

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 test Lipoprotein 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.

Primary outcome measures

  • Difference in the rate of production of VLDL Apo B [Time frame: Baseline]
  • Difference in the rate of production of VLDL Triglycerides [Time frame: Baseline]
  • Difference in the rate of production of VLDL ApoC-III and apoE [Time frame: Baseline]
  • Difference in the Fractional Catabolic Rate of VLDL Apo B [Time frame: Baseline]
  • Difference in the Fractional Catabolic Rate of VLDL Triglycerides [Time frame: Baseline]
  • Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE [Time frame: Baseline]
  • Difference in de novo lipogenesis [Time frame: Baseline]
  • Difference in liver fat [Time frame: Baseline]
  • Difference in atherogenic dyslipidemia [Time frame: Baseline]
  • Difference in insulin resistance [Time frame: Baseline]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model
Case-control

Study locations

Finland · 1 center
  • RPU Clinical and Molecular Metabolism, Biomedicum — Helsinki
Sweden · 1 center
  • Wallenberg Laboratory — Gothenburg

Publications

  • Taskinen MR, Bjornson E, Matikainen N, Soderlund S, Ramo J, Ainola MM, Hakkarainen A, Sihlbom C, Thorsell A, Andersson L, Bergh PO, Henricsson M, Romeo S, Adiels M, Ripatti S, Laakso M, Packard CJ, Boren J. Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations. JCI Insight. 2022 Oct 10;7(19):e160607. doi: 10.1172/jci.insight.160607. PMID 36040803

Identifiers

NCT: NCT04209816 · HUS/53/2017

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗