NAFLD severity and relationships with GDF-15 concentrations, PNPLA3-I148M genotype and adipose tissue biology.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. The presence of clinically significant liver fibrosis (i.e. ≥F2 fibrosis) in NAFLD predicts all-cause and disease specific mortality. This reasonably early stage of liver fibrosis may be amenable to treatments that either regress or stabilise the fibrotic liver disease preventing further progression to advanced liver fibrosis, cirrhosis, and liver failure. Obesity and type 2 diabetes mellitus (T2DM) are known risk factors associated with an increased risk of liver fibrosis. Three candidate mediators/influencing factors that may be involved in the development of liver fibrosis in NAFLD are growth differentiation factor-15 (GDF-15) concentrations, PNPLA3-I148M genotype and altered adipose tissue (AT) biology. The aims of this thesis were to explore in patients with NAFLD, whether ≥F2 liver fibrosis associates with a) GDF-15, and whether GDF-15 concentrations influences the known association between T2DM and ≥F2 liver fibrosis; b) presence of the PNPLA3-I148M variant and measures of subcutaneous AT (SAT) lipid composition; and whether the PNPLA3-I148M variant associates with alterations in SAT lipid and transcriptomic profiles; and c) alterations in genetic signatures of SAT function. Concentrations of GDF-15 were independently associated with the presence of ≥F2 liver fibrosis and influenced the association between T2DM and ≥F2 liver fibrosis. HbA1c concentrations explained one-third of the variance in GDF-15 concentrations. The composition of lipids in SAT was not linked to liver fibrosis severity, however, the presence of the PNPLA3-I148M variant was associated with increased liver fat content and enrichment of polyunsaturated fatty acids (PUFAs) in SAT triglycerides but not with alterations in SAT transcriptomic profiles. The presence ≥F2 liver fibrosis was associated with an enrichment in the expression of genes associated with inflammation and extracellular matrix remodelling in SAT. Furthermore, a gene expression signature of collagen expression in SAT was able to distinguish between patients stratified by the presence vs absence of ≥F2 liver fibrosis. Collectively, these findings provide a novel understanding for the potential role of GDF-15 concentrations, the PNPLA3-I148M genotype and adipose tissue biology in liver fibrosis and liver fat, within the spectrum of liver disease encapsulated in patients with NAFLD.

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Identifiers

ORCID for Josh Bilson: orcid.org/0000-0003-4665-3886

ORCID for Jaswinder Sethi: orcid.org/0000-0003-4157-0475

ORCID for Christopher Byrne: orcid.org/0000-0001-6322-7753

ORCID for Philip Calder: orcid.org/0000-0002-6038-710X

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