@misc{Simões_Inês_Effects_2021,
 author={Simões, Inês},
 editor={Więckowski, Mariusz Roman (1972– ) : Supervisor},
 editor={Oliveira, Paulo Jorge : Supervisor},
 address={Warsaw},
 howpublished={online},
 year={2021},
 school={Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN},
 publisher={Nencki Institute of Experimental Biology PAS},
 language={eng},
 abstract={Non-alcoholic fatty liver disease (NAFLD) affecting approximately 24% of the worldwide population is the main leading cause of chronic liver disease. The increased number of fatty liver cases considered as the hepatic manifestation of the metabolic syndrome, is rising in parallel with obesity and type 2 diabetes. This is mainly associated with the sedentary habits and overconsumption of hypercaloric diets. The initial stage of NAFLD - non-alcoholic fatty liver (NAFL) is characterized by a metabolic remodelling of the liver to compensate the overload of fat accumulation. Although, this compensatory event seems to be abolished during disease progression. Along this process, mitochondrial function impairment and an exacerbation of oxidative stress have been described to trigger hepatic signalling pathways associated with the initiation of inflammation, fibrosis and cirrhosis (transition to non-alcoholic steatohepatitis (NASH)). Despite the advances in the field, the primary mechanisms underlying the development of NAFL and its progression into NASH are complex and still incomplete. In this context, my first aim was to study the hepatic and mitochondrial redox-associated alterations in a NAFL stage. I have characterized hepatic proteome, mitochondrial structure and function, reactive oxygen species (ROS) production and antioxidant defences in a mouse model of early NAFLD stage. Induction of NAFL resulted from a chronic feeding (16 weeks) of mice with different diets: high-fat, high-sucrose or high-fat plus high-sucrose diets. I have shown (see Chapter 1), that no excess of mitochondrial ROS took place in NAFL. Therefore, I have suggested that other organelles as peroxisomes rather than mitochondria contribute to hepatic oxidative stress. Moreover, I established that fat and sucrose (components of Western diet) differentially impair autophagy. In the second aim, I investigated the specific end-points for mitochondrial dysfunction that represent “a point of no return” and which drive disease progression along time. NAFL development has been studied with the use Western diet (WD) in an early NAFLD stage mice model. The combination of high-fat and high-sucrose representing Western diet good resemble human NAFLD features of the disease development. In this part of my thesis (see Chapter 2), I demonstrated for the first time the sequential events of mitochondrial alterations during NAFL development and progression. I showed that in a more progressive NAFL stage previously observed mitochondrial adaptation in NAFL was followed by a progressive decrease of mitochondrial respiration concomitant with a higher susceptibility to mitochondrial permeability transition pore (mPTP) opening. Importantly, it was proven that mitochondrial ROS are not the first hit causing disease progression. Instead, my findings continue to support the role of peroxisomes as possible contributors to the hepatic oxidative damage in the origin of hepatic injury and progression of the disease.},
 title={Effects of Western diet in the development and progression of Non-alcoholic fatty liver disease : PhD thesis},
 type={Text},
 URL={http://www.rcin.org.pl/Content/234680/Thesis_25.11.21_Ines%20Simoes%20FINAL.pdf},
 keywords={Liver autophagy, Metabolism, Mitochondria, Non-alcoholic fatty liver, Oxidative stress, Peroxisomes},
}