Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

Insulin Resistance Clinical Trial

— VARKIN  

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04209816
• Other study ID #: HUS/53/2017
• Status: Enrolling by invitation
• Start date: December 1, 2019
• Est. completion date: December 2028

Study information

• Verified date: September 2023
• Source: Helsinki University Central Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 100
• Est. completion date: December 2028
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Atherogenic Dyslipidemia
• Dyslipidemias
• Fatty Liver
• Insulin Resistance
• Non-alcoholic Fatty Liver
• Non-alcoholic Fatty Liver Disease

Intervention

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.

Locations

Country	Name	City	State
Finland	RPU Clinical and Molecular Metabolism, Biomedicum	Helsinki
Sweden	Wallenberg Laboratory	Gothenburg

Sponsors (2)

Lead Sponsor	Collaborator
Marja-Riitta Taskinen	Göteborg University

Countries where clinical trial is conducted

Finland,  Sweden, 

Outcome

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