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Metabolic changes in non-alcoholic fatty liver disease – Interactions with genes regulating fatty acid metabolism

In the doctoral thesis by Paula Walle, Lic Med, several alterations in endogenous fatty acid metabolism linked with NAFLD that were associated with weight loss and dietary factors were observed. These findings suggest that changes in fatty acid metabolism and the genotype of genes regulating fatty acid metabolism potentially contribute to the progression of NAFLD.

The prevalence of overweight and obesity has increased globally, and more than 600 million adults are estimated to be obese. Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of 25% based on imaging studies. Liver steatosis is defined as the presence of steatosis in >5% of hepatocytes. Non-alcoholic steatohepatitis (NASH) is diagnosed when there is histological evidence of inflammation and ballooning in addition to steatosis, with or without fibrosis. NAFLD is associated with increased mortality and a higher prevalence of hypertension, type 2 diabetes, increased insulin resistance, hypertriglyceridemia, and lower high-density lipoprotein levels. The key feature of NAFLD is the accumulation of triglycerides into hepatocytes, and the pathogenesis of NAFLD is associated with several disturbances in fatty acid metabolism, modified by lifestyle factors and genetic variation.

The aim of the doctoral thesis was to study the role of fatty acid metabolism and expression of genes participating in fatty acid metabolism in NAFLD. Moreover, the effects of bariatric surgery on fatty acid metabolism were studied. The primary study population of this thesis consisted of subjects from the Kuopio Obesity Surgery Study (KOBS).

The study demonstrated several alterations in fatty acid metabolism and endogenous desaturase activities that associate with NASH, independently of obesity and diet (n=92 from KOBS). Obese individuals with NASH had higher estimated activities of delta-6 desaturase and stearoyl-CoA desaturase 1, and lower activity of delta-5 desaturase than individuals with a normal liver. Moreover, NASH was associated with higher hepatic mRNA expression of FADS1, FADS2, and SCD. Finally, some of the differences in fatty acid metabolism that associated with NASH in obese individuals, were also observed in individuals with high alanine aminotransferase in a population-based study cohort (769 men from the cross-sectional Metabolic Syndrome in Men Study (METSIM)).

Since DNA methylation in the FADS gene cluster has previously been associated with genetic variants and alterations in desaturase activities, factors regulating DNA methylation of the CpG sites annotated to the FADS1/2 genes were studied (n=95 from KOBS). This study showed association of higher hepatic FADS2 mRNA expression and serum delta-6 desaturase activity with lower levels of DNA methylation in CpG sites annotated to FADS2. Moreover, DNA methylation levels of FADS2 were linked with the FADS2 genotype.

In this thesis, it was observed that bariatric surgery induces beneficial changes in the serum fatty acid profile that associate with alterations in endogenous fatty acid metabolism in response to surgery and changes in the diet and were closely related to weight loss (n=122 from KOBS). Moreover, changes in the serum fatty acid profile after bariatric surgery are similar to those observed after weight reduction through healthy diet and increased physical activity (122 people with an elevated risk of type 2 diabetes from the Finnish Diabetes Prevention Study (DPS)), at least if the intake of non-tropical vegetable oils and n-3 fatty acids is sufficient.

The doctoral dissertation of MD Paula Walle, entitled Metabolic changes in non-alcoholic fatty liver disease – Interactions with genes regulating fatty acid metabolism, will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Carel le Roux of the University College Dublin, and the Custos will be Professor Jussi Pihjalamäki of the University of Eastern Finland.

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Walle, Paula. Metabolic changes in non-alcoholic fatty liver disease: Interactions with genes regulating fatty acid metabolism