Obesity is increasing worldwide. The addition of excess calorie intake and unhealthy human behavior leads to also other diseases such as metabolic syndromes and liver disease such as non-alcoholic fatty liver disease. Furthermore, the accumulation of fat triggers specific mechanisms that, if prolonged, can cause tissue damage. For instance, the innate immune system becomes agitated in patients with NAFLD or obesity due to excessive fat accumulation. This leads to inflammation in specific tissues and infiltration of other immune cells. One of the main immune cells are neutrophils, which secrete a protease enzyme called protease neutrophil elastase. Interestingly, there have been studies conducted that have shown that when neutrophil elastase is knocked out in mouse models that mimic NAFLD, there seems to be a protective effect occurring in the body and lessen tissue scarring. A possible explanation, and the aim of this thesis, is to explore if autophagy is regulated and thus plays a role in protecting liver from inflammation and fibrosis. Western blotting approach was used to test this hypothesis. The protein samples that are used are extracted from neutrophil elastase knockout mice that have been fed a high-fat high-fructose diet and compare them to samples from wild-type control mice that have been fed a normal chow diet, high-fat diet, and high fat high fructose diet. The results indicated that potential upregulation of the autophagy pathway in the liver of neutrophil elastase knockout mice and more studies would need before accurately and reliably acknowledging the alternation of the autophagy pathway in the liver from mouse model of NAFLD and when neutrophil elastase is knocked out. / 2023-12-10T00:00:00Z

Nonalcoholic fatty liver disease (NAFLD) afflicts approximately a quarter of the world’s general population and more than half of the world’s obese population. The disease is characterized by a spectrum of liver pathologies, ranging from simple steatosis or the accumulation of fat within hepatic tissue to steatohepatitis comprised of inflammation and fibrosis, also known as NASH. Simple steatosis is relatively asymptomatic and is considered benign, but NASH poses great risk for advanced forms of liver disease, such as cirrhosis and hepatocellular cancer. Obstructive sleep apnea(OSA) is a respiratory disorder involving the recurrent collapse of the upper airway during sleep. Consequently, the patient experiences constant arousals due to constant blockage followed reopening of the airway. Aside from poor quality and disruption of sleep, chronic intermittent hypoxia (CIH) is also present during OSA. The presence of CIH leaves many vital organs deprived of adequate oxygen to carry out normal physiological function. In response to this hypoxic state, the body upregulates many transcription factors, many of which control inflammatory processes. In recent studies, chronic and recurrent hypoxia generated from OSA has been implicated in the onset and progression of NAFLD. The pathogenesis of NAFLD is believed to be associated with metabolic imbalances, mainly obesity and insulin resistance, both of which also overlap with OSA. These conditions are the main factors in predisposing a patient suffering from OSA to the effects of CIH. Multiple lines of evidence suggest that CIH may accelerate the development of NAFLD through 1) Lipolysis of hepatic adipose tissue and increased hepatic free fatty acids; 2) Upregulation of lipid biosynthetic through CIH; 3) Upregulation of hypoxia-inducible factor 1-alpha by CIH inducing liver inflammation and fibrosis. The primary focus of this thesis will attempt to determine a possible link between OSA and NAFLD. Through citation of prior scientific studies, it will formulate the theory of OSA as a predisposing factor in the heightened risk of NAFLD pathogenesis and development to more severe, terminal stages. Primarily, the review of literature will highlight the metabolic imbalances of obesity and insulin resistance and how each is related to OSA and NAFLD. Ultimately, deposition of fat and inflammation triggered through various chemical factors connected to OSA will depict both the generation and progression of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) and has emerged as a risk factor for more critical clinical conditions. However, the underlying mechanisms of NAFLD pathogenesis are not fully understood. In this study, expression of proteins associated with endoplasmic reticulum (ER) stress, apoptosis and autophagy were analyzed in normal, NAFL and NASH human livers by western blotting. Levels of some ER stress-transducing transcription factors, including cleaved activating transcription factor 6, were higher in NASH than in the normal tissues. However, the expression of a majority of the ER chaperones and foldases analyzed, including glucose-regulated protein 78 and ER protein 44, was lower in NASH than in the normal tissues. Levels of apoptosis markers, such as cleaved poly (ADP-ribose) polymerase, were also lower in NASH tissues, in which expression of some B-cell lymphoma-2 family proteins was up-or down-regulated compared to the normal tissues. The level of the autophagy substrate p62 was not different in NASH and normal tissues, although some autophagy regulators were up-or down-regulated in the NASH tissues compared to the normal tissues. Levels of most of the proteins analyzed in NAFL tissues were either similar to those in one of the other two types, NASH and normal, or were somewhere in between. Together, these findings suggest that regulation of certain important tissues processes involved in protein quality control and cell survival were broadly compromised in the NAFLD tissues.

Background/objectives The relationship between nonalcoholic fatty liver disease (NAFLD) and albuminuria has been shown in many epidemiologic studies, although the results were inconsistent. This meta-analysis was conducted to summarize all available data and to estimate the risk of albuminuria among patients with NAFLD. Methods Comprehensive literature review was conducted utilizing Medline and Embase database through January 2018 to identify studies that compared the risk of albuminuria among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Results Nineteen studies (17 cross-sectional studies and two cohort studies) with 24 804 participants fulfilled the eligibility criteria and were included in this meta-analysis. The risk of albuminuria among patients with NAFLD was significantly higher than those without NAFLD with the pooled odds ratio (OR) of 1.67 [95% confidence interval (CI): 1.32-2.11]. Subgroup analysis demonstrated the significantly increased risk of albuminuria among patients with NAFLD without diabetes with pooled OR of 2.25 (95% CI: 1.65-3.06). However, we found no significant association between albuminuria and NAFLD among diabetic patients [pooled OR 1.28 (95% CI: 0.94-1.75)]. Conclusion A significantly increased risk of albuminuria among patients with NAFLD was observed in this meta-analysis. Physicians should pay more attention to the early detection and subsequent treatment of individuals with microalbuminuria especially in patients with NAFLD.

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The body encounters an innumerable amount of foreign substances, termed xenobiotics, which it must remove in order to prevent damage to cells and organs. This system of removal is a collection of processes known as ADME (absorption, distribution, metabolism, and excretion). The dynamics of ADME ultimately determine the fate, or pharmacokinetics, of a xenobiotic in the body whether it be an administered pharmaceutical or a potentially harmful toxicant. The major cellular effectors of ADME are the drug metabolizing enzymes (DMEs) and transporters. DMEs function to transform xenobiotics into a metabolite that is more suitable for excretion, whereas drug transporters serve a two-fold function. They may facilitate the uptake of the xenobiotic into the cell so that it can be acted upon by DMEs, or they may function to actively secrete xenobiotics and metabolites from the cell, encouraging their removal from the body. Any perturbations in the expression or function of these critical cellular effectors can result in the diminished therapeutic effect of a pharmaceutical via accelerated removal from the body, or increased toxicity of a pharmaceutical or toxicant due to retention in the body and increased exposure.Perturbations in the ADME processes may result in adverse drug reactions (ADRs) which are an unintended response to a pharmaceutical when administered at the recommended dose. In the last reporting year, the USFDA documented 471,291 serious ADRs causing hospitalization or permanent disabilities, of which 82,724 resulted in death. ADRs can be categorized as two types: dose-related ADRs, and those that are generally unpredictable and mostly occur in susceptible individuals. The major factors that make a person susceptible to ADRs are genetics and disease; however, genetics account for only a small proportion. This dissertation is focused on the contribution of an environmentally-derived component, particularly liver disease, to the occurrence of ADRs. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease of industrialized nations. It represents a spectrum of damage progressing to the severe stage of nonalcoholic steatohepatitis (NASH), and is closely related to obesity and type 2 diabetes. The following studies have determined the effect of NAFLD and NASH on DMEs and transporters, and demonstrated the propensity for NASH to result in serious ADRs.

Nonalcoholic fatty liver disease (NAFLD) has become a worldwide, chronic liver disease of increasing clinical significance. It is closely associated with the rising epidemics of obesity and insulin resistance. Up to 17% of the United States population may progress from the disease stage characterized as simple, benign steatosis to the more severe, inflammatory stage of nonalcoholic steatohepatitis (NASH). This progression occurs through 2nd 'hits' of increased oxidative stress and inflammation to a liver that has been sensitized by lipotoxic stress. NASH is also characterized by increased collagen deposition resulting in fibrosis and architectural rearrangement of the liver. Progressive NAFLD is currently recognized as an important contributor to the development of cryptogenic cirrhosis and subsequent liver-related mortalities (estimated at 30-40% in these patients).The pathological progression of NAFLD, as described by the 'two hit' hypothesis, characterizes the different stages of liver injury. However, the mechanism(s) responsible for the progression to NASH are unknown. Profiling global gene expression and metabolite patterns in human liver samples representing the full spectrum of progressive human NAFLD may reveal potential mechanisms of progressive disease. Human liver samples representing each stage of NAFLD progression were analyzed by methodologies such as high-throughput microarrays, high resolution mass spectrometry, and protein immunoblot techniques. Bioinformatics tools and gene expression/regulation database software were utilized in several studies to characterize the altered hepatic profiles of these patients. Hepatic transcriptomic profiles of ADME (absorption, distribution, metabolism and elimination) and ER (endoplasmic reticulum) stress response genes exhibited initiated hepatoprotective responses in patients with NASH. The endogenous pathways of BA (bile acid) synthesis and BCAA (branched chain amino acid) metabolism also showed evidence of coordinately regulated alterations in response to disease-induced stress in NASH. The transcriptional regulation of the investigated pathways was confirmed by transcription factor binding sites enrichment analysis. The collective response to hepatic stress in human NAFLD, demonstrates a coordinated, hepatoprotective intent that may be utilized for future therapeutics in the battle against progressive liver disease.

ABCD2 (D2) is a peroxisomal ATP binding cassette (ABC) transporter that is expressed in brain, adrenal and liver. D2 is transcriptionally regulated by key transcriptional factors that control lipid and glucose metabolism. Therefore, we examined its role in adipose tissue. These studies revealed that D2 is highly abundant in adipose tissue and upregulated during adipogenesis. However, D2 deficiency does not affect either adipogenesis or lipid accumulation. An examination of the lipid profile of adipose tissue revealed the accumulation of C20 and C22 fatty acids in D2 deficient (D2‐/‐) mice. When challenged with a diet enriched in erucic acid (C22:1, 10% kcal), this lipid accumulated in both liver and adipose tissue. Following 8 weeks of diet, D2‐/‐ mice showed increased adiposity, glucose intolerance, dyslipidemia and steatosis. Analysis of the hepatic lipid profile showed significant changes away from poly unsaturated fatty acids (PUFAs) and toward C18‐22 mono‐unsaturated fatty acids (MUFA). RT‐PCR of the mRNA from the adipose tissue and liver revealed significant changes in lipogenic (ACC, SCD1 & 2) and PUFA synthesis (Δ5 & 6‐desaturase) genes in D2‐/‐ mice. The molecular mechanisms by which D2 regulates lipid metabolism in adipose tissue remains unclear. To explore potential mechanisms, the subcellular localization of D2 in adipose tissue was determined. Our results demonstrated that D2 resides in a distinct subclass of peroxisomes that does not containing classical peroxisomal markers such as pex19 or PMP70, but are positive for pex14. In conclusion, our studies reveal a novel role of D2 and peroxisomes in the protection from disruptions of lipid metabolism induced by dietary erucic acid and that D2 resides in a unique compartment within adipocytes that plays a yet to be elucidated role in the regulation of lipid metabolism.

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