Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

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

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.

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