Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

• Conditions: Non-alcoholic Fatty Liver; Insulin Resistance; Atherogenic Dyslipidemia
• Interventions: Diagnostic Test: Lipoprotein kinetics

• Registration Number: NCT04209816
• Lead Sponsor: Marja-Riitta Taskinen

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-12-01
• Study First Submitted: 2019-12-19
• Study First Submitted QC: 2019-12-20
• Study First Posted: 2019-12-24
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-21
• Last Update Posted: 2023-09-22
• Primary Completion: 2024-06
• Study Completion: 2028-12

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 100

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

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
ApoC-III LOF	Lipoprotein kinetics	Carriers of apo-CIII loss-of-function mutation
Control	Lipoprotein kinetics	No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation
TM6SF2-KK	Lipoprotein kinetics	Carriers of TM6SF2 E167K mutation
PNLPLA3-MM	Lipoprotein kinetics	Carriers of PNLPLA3 I148M mutation
ApoE variants	Lipoprotein kinetics	Carriers of E2/2, E3/3 or E4/4 mutation
LIPG	Lipoprotein kinetics	LIPG gene LOF or GOF variant carriers
ApoC-III GOF	Lipoprotein kinetics	Carriers of apo-CIII gain-of-function mutation

Primary Outcome Measures

Name	Time	Method
Difference in de novo lipogenesis	Baseline	Measure of newly synthesized triglycerides in VLDL, μmol/l
Difference in the rate of production of VLDL ApoC-III and apoE	Baseline	Production rate, mg/kg/day
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 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
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 apoprotein C concentration	Baseline	ApoC, mg/dl
Difference in liver fat	Baseline	Percentage of liver fat measured with magnetic resonance spectroscopy
Lipolytic activity	Baseline	Measured lipoprotein lipase activity, mU/ml
Hepatic lipase activity	Baseline	Measured hepatic lipase activity, mU/ml
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

Trial Locations

Locations (2)

Wallenberg Laboratory; 🇸🇪 Gothenburg, Sweden

RPU Clinical and Molecular Metabolism, Biomedicum; 🇫🇮 Helsinki, Finland