AbstractsBiology & Animal Science

Molecular Link between Lipid Metabolism and Energy Homeostasis

by Pirkka-Pekka Laurila




Institution: University of Helsinki
Department: Institute of Biomedicine, Lääketieteellisen genetiikan ja perinnöllisyyslääketieteen osasto; National Institute for Health and Welfare, Genomics and Biomarkers Unit
Year: 2015
Keywords: lääketiede
Record ID: 1135885
Full text PDF: http://hdl.handle.net/10138/153610


Abstract

Cardiovascular disease is the leading cause of death worldwide, and is characterized by disturbances in lipid metabolism. High blood LDL cholesterol is the most important risk factors for atherosclerosis, a pathological state in which the circulating lipid molecules accumulate in the blood vessel wall. Blood levels of HDL cholesterol are inversely associated with cardiovascular risk, and low HDL-cholesterol is a significant risk factor for cardiovascular disease. In this thesis, new genes predisposing to low HDL-cholesterol level were searched using genome-wide association analysis in Finnish individuals with extremely low or high HDL-cholesterol. Several new genes predisposing to low HDL-cholesterol were discovered, of which many were known to be associated with immune system and inflammatory reaction of the body, but their role in cholesterol metabolism has not previously been characterized. Some of the subjects appeared to be genetically more prone to inflammation than others, especially in the blood and adipose tissue. The more inflammation inducing genetic variants one had, the stronger was the inflammatory state of the body, especially in blood and adipose tissue, and the lower the HDL-cholesterol level. The inflammation may block the transport of cholesterol from vessel walls to circulation leading to lower HDL-cholesterol levels in the circulation. This thesis also examined the composition of HDL particles by determining the concentration of all know lipid species in HDL particles. The quality of HDL particles appeared to vary considerably. In individuals, whose HDL-cholesterol levels were low, the quality of HDL particles was also impaired; they contained smaller amounts of plasmalogens which are fat molecules known to be antioxidant and thus protective to arteries. In individuals with high HDL-cholesterol levels in the circulation, the lipid composition of the HDL particle was more beneficial regarding heart disease risk. This thesis further demonstrates that not only the quantity but also the quality of HDL particles is genetically regulated. The genetic variants regulating the level of HDL-cholesterol also govern its quality, highlighted by inflammation-increasing genetic variants also impairing HDL quality. This thesis work provides novel insights about the molecular background of HDL cholesterol and validates the strong link between inflammation and low HDL-cholesterol levels. The studies show how genetically induced inflammation reduces blood HDL-cholesterol levels and impairs HDL particle quality, potentially predisposing to cardiovascular disease. Sydän- ja verisuonitaudit on maailman yleisin kuolinsyy, joille voivat altistaa häiriöt veren rasva-aineenvaihdunnassa. Veren suuri LDL-kolesterolipitoisuus on merkittävimpiä riskitekijöitä valtimokovettumataudille eli ateroskleroosille, jossa verenkierron rasvat kertyvät verisuonen seinämään. Veren HDL-kolesterolin taso on käänteisesti yhteydessä sydän- ja verisuonitaudin riskiin, ja pieni HDL-kolesterolipitoisuus on huomattava sydän- ja…