Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

NCT ID: NCT04209816

Last Updated: 2023-09-22

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-12-01
• Study Completion Date: 2028-12-31

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.

Conditions

Non-alcoholic Fatty Liver; Atherogenic Dyslipidemia; Insulin Resistance

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

ApoC-III LOF

Carriers of apo-CIII loss-of-function mutation

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

ApoC-III GOF

Carriers of apo-CIII gain-of-function mutation

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

TM6SF2-KK

Carriers of TM6SF2 E167K mutation

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

PNLPLA3-MM

Carriers of PNLPLA3 I148M mutation

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

Control

No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

ApoE variants

Carriers of E2/2, E3/3 or E4/4 mutation

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

LIPG

LIPG gene LOF or GOF variant carriers

Lipoprotein kinetics

Intervention Type: DIAGNOSTIC_TEST

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.

ANGPTL3 or ANGPTL8

ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers

No interventions assigned to this group

Interventions

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.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

Measurement of de novo lipogenesis; Measurement of lipolytic activity; Measurement of liver fat

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Göteborg University

OTHER

Sponsor Role: collaborator

Marja-Riitta Taskinen

OTHER

Sponsor Role: lead

Responsible Party

Marja-Riitta Taskinen

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

RPU Clinical and Molecular Metabolism, Biomedicum

Helsinki, , Finland

Wallenberg Laboratory

Gothenburg, , Sweden

Countries

Finland; Sweden

References

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.

Reference Type: DERIVED

PMID: 36040803 (View on PubMed)

Other Identifiers

HUS/53/2017

Identifier Type: -

Identifier Source: org_study_id