Exploring lipoprotein characteristics in human cardiometabolic disease

Background: Atherosclerosis underlies most cases of cardiovascular disease (CVD) which remains the principal cause of global mortality. CVD is significantly linked to cardiometabolic diseases such as diabetes and obesity. These disorders precipitate a cascade of metabolic dysregulations, including insulin resistance and altered lipid metabolism, culminating in modified lipoprotein profiles.

Aim: Dissecting the characteristics of lipoproteins in the context of cardiometabolic diseases and their contribution to atherogenesis.

Methods: The thesis is based upon five papers. I. Assessment of the impact of a novel potential therapeutic agent on hepatic lipid metabolism using modified mRNA molecules in human hepatoma cell lines. II. Characterization of HDL in systemic arterial and coronary blood from patients with Non-ST-Elevation Myocardial Infarction (NSTEMI). III. Evaluation of the influence of clustered cardiometabolic risk factors on the functional properties of HDL. IV. Investigation into mechanisms of lipoprotein retention in type 2 diabetes through analyses of lipoproteins in serum and interstitial fluid. V. Characterization of postprandial lipoproteins in serum and interstitial fluid among healthy controls and individuals with type 2 diabetes.

Results: Key findings from the thesis papers were I. The overexpression of TGIF1 protein in hepatoma cells induced a favorable lipid profile alteration. II. Notable differences in HDL properties were found between coronary and systemic circulation in the immediate aftermath of NSTEMI, unrelated to HDL levels. III. Cardiometabolic risk factors exert a progressive negative impact on HDL function, with a major contribution of abdominal obesity to alterations in reverse cholesterol transport. IV. An apparent increase in vascular retention of atherogenic lipoproteins was seen in type 2 diabetes, manifested by reduced ApoB-containing lipoproteins in interstitial fluid concomittant with increased LDL affinity for arterial proteoglycans. Similar changes were observed with increasing age in controls. V. Distinct postprandial alterations in serum and interstitial fluid revealed atherogenic postprandial lipoprotein modifications in Type 2 diabetes.

Conclusion: This thesis accentuates the relationship between lipoprotein properties and atherosclerosis in the context of cardiometabolic disorders. The insights highlight the importance of qualitative lipoprotein evaluation beyond conventional quantitative lipoprotein analysis. Such analyses should improve preventive strategies, including cardiovascular risk assessment and new therapeutic interventions.

List of scientific papers

I. Härdfeldt J, Hodson L, Larsson L, Pedrelli M, Pramfalk C. Effects on hepatic lipid metabolism in human hepatoma cells following overexpression of TGFβ induced factor homeobox 1 or 2. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 May;1864(5):756-762.
https://doi.org/10.1016/j.bbalip.2019.02.009

II. Cariello M, Salvia R, Härdfeldt J, Piglionica M, Rutigliano D, Caldarola P, Ossoli A, Vacca M, Graziano G, Battaglia S, Zerlotin R, Arconzo M, Crudele L, Sabbà C, Calabresi L, Moschetta A. Intracoronary monocyte expression pattern and HDL subfractions after non ST elevation myocardial infarction. Biochim Biophys Acta Mol Basis Dis. 2021 Jun 1;1867(6):166116.
https://doi.org/10.1016/j.bbadis.2021.166116

III. Härdfeldt J, Cariello M, Simonelli S, Ossoli A, Scialpi N, Piglionica M, Pasculli E, Noia A, Berardi E, Suppressa P, Piazzolla G, Sabbà C, Calabresi L, Moschetta A. Abdominal obesity negatively influences key metrics of reverse cholesterol transport. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Feb;1867(2):159087.
https://doi.org/10.1016/j.bbalip.2021.159087

IV. Björklund P*, Härdfeldt J*, Straniero S, Äikäs L, Öörni K, Rudling M, Angelin B. Transvascular retention of atherogenic lipoproteins in type 2 diabetes relates to their enhanced proteoglycan-binding susceptibility. *Co-First Authors. [Manuscript]

V. Härdfeldt J*, Björklund P*, Straniero S, Rudling M, Angelin B. Fasting and postprandial lipoproteins in Interstitial Fluid in Type 2 Diabetes. *Co-First Authors. [Manuscript]