Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

NCT04209816 | Enrolling By Invitation

• 1 other identifier: HUS/53/2017
• Study Type: observational
• Target: 100
• Locations: 2 countries
• Sites: 2

Brief Summary

The aims of the study are:

1. 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. 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. 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. 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

Keywords

Non-alcoholic Fatty Liver; Apoproteins; Genetic variants

Outcome Measures

Primary Outcomes (18)

• Difference in the rate of production of VLDL Apo B

  Production rate, mg/day

  Baseline

• Difference in the rate of production of VLDL Triglycerides

  Production rate, mg/kg/day

  Baseline

• Difference in the rate of production of VLDL ApoC-III and apoE

  Production rate, mg/kg/day

  Baseline

• Difference in the Fractional Catabolic Rate of VLDL Apo B

  Rate of disappearance, pools/day

  Baseline

• Difference in the Fractional Catabolic Rate of VLDL Triglycerides

  Rate of disappearance, pools/day

  Baseline

• Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE

  Rate of disappearance, pools/day

  Baseline

• Difference in de novo lipogenesis

  Measure of newly synthesized triglycerides in VLDL, μmol/l

  Baseline

• Difference in liver fat

  Percentage of liver fat measured with magnetic resonance spectroscopy

  Baseline

• Difference in atherogenic dyslipidemia

  Remnant lipoproteins and lipoprotein fraction composition, mg/L

  Baseline

• Difference in insulin resistance

  Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

  Baseline

• Difference in apoprotein A concentration

  ApoA, mg/dl

  Baseline

• Difference in apoprotein B concentration

  ApoB, mg/dl

  Baseline

• Difference in apoprotein C concentration

  ApoC, mg/dl

  Baseline

• Difference in apoprotein E concentration

  ApoE, mg/dl

  Baseline

• Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B

  Rate of turnover, pools/day

  Baseline

• Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B

  Rate of turnover, pools/day

  Baseline

• Lipolytic activity

  Measured lipoprotein lipase activity, mU/ml

  Baseline

• Hepatic lipase activity

  Measured hepatic lipase activity, mU/ml

  Baseline

Study Arms (8)

ApoC-III LOF

Carriers of apo-CIII loss-of-function mutation

Diagnostic Test: Lipoprotein kinetics

ApoC-III GOF

Carriers of apo-CIII gain-of-function mutation

Diagnostic Test: Lipoprotein kinetics

TM6SF2-KK

Carriers of TM6SF2 E167K mutation

Diagnostic Test: Lipoprotein kinetics

PNLPLA3-MM

Carriers of PNLPLA3 I148M mutation

Diagnostic Test: Lipoprotein kinetics

Control

No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation

Diagnostic Test: Lipoprotein kinetics

ApoE variants

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

Diagnostic Test: Lipoprotein kinetics

LIPG

LIPG gene LOF or GOF variant carriers

Diagnostic Test: Lipoprotein kinetics

ANGPTL3 or ANGPTL8

ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers

Interventions

Lipoprotein kinetics 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.

Also known as: Measurement of de novo lipogenesis, Measurement of lipolytic activity, Measurement of liver fat

ApoC-III GOF; ApoC-III LOF; ApoE variants; Control; LIPG; PNLPLA3-MM; TM6SF2-KK

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Ambulatory outpatients who are recruited from our previous study investigating familial dyslipidemia where exome sequency has been performed to explore genes involved in lipid metabolism (HUCH Ethics Committee, Department of Medicine: 108/1996, follow-up studies Dnro 170/E5/02, Drno 215/13/03/01/2009, Drno 144/13/03/01/2011 and HUCH Coordinating Ethics Committee Drno 184/13/03/00/2012, and Drno 183/13/03/00/2012). All subjects who have given oral consent that they can be informed about new studies focused on lipid metabolism will be contacted. To recruite the subjects we will use the invitation letter and follow up all the policy as stipulated in the Finnish biobank law (688/2012) (http//nationalbiobanks.fi/index.php./studies2/7-finrisk).

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Marja-Riitta Taskinen: lead
• Göteborg University: collaborator

Study Sites (2)

RPU Clinical and Molecular Metabolism, Biomedicum

Helsinki, Finland

Location

Wallenberg Laboratory

Gothenburg, Sweden

Location

Related Publications (1)

• 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 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Plasma and serum samples

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Insulin Resistance

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 19, 2019
• First Posted: December 24, 2019
• Study Start: December 1, 2019
• Primary Completion: June 1, 2024
• Study Completion (Estimated): December 1, 2028
• Last Updated: September 22, 2023

Record last verified: 2023-09

Locations

FI (1); SE (1)