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.

No description available.

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.

Many individuals presumed to have non-alcoholic fatty liver disease (NAFLD) consume moderate amounts of alcohol; however, little is known regarding patterns of alcohol use and how drinking behaviors may influence liver fat. We conducted a cross-sectional study of 2,475 participants of the Framingham Heart Study who underwent computed tomography (CT) to define liver fat. We performed multivariable-adjusted logistic regression models for the association between different alcohol drinking patterns, including the average alcoholic drinks/week, frequency of alcohol use, usual quantity of alcohol consumed, maximum drinks consumed in 24 hours, and binge drinking behavior, and CT-defined hepatic steatosis. We excluded heavy alcohol users defined as women who drink > 14 drinks/week and men who drink > 21 drinks/week. We also performed an analysis specific to beverage type (beer, wine, or liquor/spirit drinks).The prevalence of hepatic steatosis in our study sample (mean age ± standard deviation (SD) 49.8±10.2, 50.3% women) was 17.5%. Among individuals with presumed NAFLD, binge drinking occurred in 25.4% of individuals. In adjusted models, the odds of hepatic steatosis increased by 20% for each SD increase in the number of alcoholic drinks consumed per week (OR 1.20; 95% confidence interval (CI) 1.08, 1.36). Frequency of alcohol use (drinking days/week) was also associated with hepatic steatosis (OR 1.09; 95% CI 1.03, 1.15). The odds of hepatic steatosis increased by 15% for each SD increase in the maximum drinks per week (OR 1.15; 95% CI 1.02, 1.30). In the beverage specific analysis, alcohol use patterns were associated with hepatic steatosis among beer drinkers, but no significant associations were observed among wine drinkers. Conclusions: Even after excluding heavy alcohol users from our sample, alcohol use contributed to liver fat, which suggests alcohol-related liver fat may be present among individuals presumed to have NAFLD. Additional prospective studies are needed to validate our findings and to determine if more comprehensive alcohol use screening tools should be used in practice or clinical trial settings. / 2020-06-03T00:00:00Z

京都大学 / 0048 / 新制・論文博士 / 博士(農学) / 乙第13019号 / 論農博第2829号 / 新制||農||1042(附属図書館) / 学位論文||H28||N4965(農学部図書室) / 32947 / (主査)教授 久米 新一, 教授 松井 徹, 教授 祝前 博明 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20560号 / 医博第4245号 / 新制||医||1022(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 柳田 素子, 教授 西渕 光昭 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Nonalcoholic fatty liver disease is a common condition associated with metabolic syndrome. It is the most common cause of elevated liver enzymes in U.S. adults, and is diagnosed after ruling out other causes of steatosis (fatty infiltration of liver), particularly infectious hepatitis and alcohol abuse. Liver biopsy may be considered if greater diagnostic and prognostic certainty is desired, particularly in patients with diabetes, patients who are morbidly obese, and in patients with an aspartate transaminase to alanine transaminase ratio greater than one, because these patients are at risk of having more advanced disease. Weight loss is the primary treatment for obese patients with nonalcoholic fatty liver disease. Medications used to treat insulin resistance, hyperlipidemia, and obesity have been shown to improve transaminase levels, steatosis, and histologic findings. However, no treatments have been shown to affect patient-oriented outcomes.

BACKGROUND: There has been renewed interest in the study of brown adipose tissue (BAT) as a potential therapeutic target for obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). There is now much evidence to suggest that BAT is not only important in thermogenesis but also plays an important role in metabolism. In adults, cold-induced BAT activation has led to a significant increase in insulin sensitivity and energy expenditure as well as decreased blood sugar levels. Thus, it is important to identify factors associated with these metabolic disorders such as the presence and activity of BAT to better understand if and how BAT can be targeted to treat these disorders. However, as a potential therapeutic target, it is important to develop accurate, precise, robust and reproducible non-invasive modalities to measure BAT. PROJECT OBJECTIVES: 1) Develop and assess protocols for the use of MRI in measuring BAT characteristics and activity 2) Examine the relationship between BAT MR outcomes and known covariates such as age, sex, body fat percentage and outdoor temperature in adult humans 3) Determine if there is any association between BAT outcomes and liver fat in adult humans, before and after adjusting for potential covariates of liver fat such as age, sex and body fat percentage METHODS: In total, 36 healthy participants (i.e. no conditions or medications that could influence BAT metabolism and/or liver disease) aged 18 to 60 years were recruited to this cross-sectional study. There were two study visits. In visit 1, anthropometrics (i.e. height, weight and waist circumference), blood pressure and body composition (via dual x-ray energy absorptiometry) were measured. Additionally, fasting bloodwork was collected and a 75-g oral glucose tolerance test (OGTT) was administered. During visit 2, participants were exposed to a standardized cold exposure set at 18°C for 3 hours using a water-perfused suit. MRI scans were acquired to evaluate changes in fat-fraction (FF%) and T2* relaxation (T2*) (BAT MR outcomes), liver fat and abdominal fat after a cold exposure. During the cold exposure protocol, mean skin temperature (MST) was monitored using 12 wireless temperature loggers placed at different sites of the body while electromyography (EMG) was used to measure shivering intensity. RESULTS: In the current study, an MRI protocol capable of detecting BAT in the supraclavicular (SCV) region was developed. This protocol included the use of FF and T2* masks to more accurately characterize BAT in the SCV region. Additionally, the MR segmentation protocol was found to be very reliable, as demonstrated by excellent ICC values (i.e. ICCagreement and ICCconsistency ≥ 0.90) for all BAT MR outcomes irrespective of cold exposure. As expected, FF% (mean difference = -2.97; p < 0.0001*) and T2* (mean difference = -0.84; p < 0.0001*) values in the SCV significantly decreased after cold exposure, consistent with BAT activation. Furthermore, the decline in both FF% and T2* after cooling was specific to the SCV region, as these changes did not occur in the posterior neck fat. In examining the relationship between BAT MR outcomes and known covariates of BAT (i.e. age, sex, body fat percentage and outdoor temperature), it is important to note that lower FF% or T2* values are reflective of a browner phenotype while a greater reduction in FF% is indicative of higher BAT activity. BAT characteristics (A: pre-cold FF%; B: pre-cold T2*) and BAT activity (C: FF% reduction) were correlated with age (A: r = 0.54; p = 0.0007*; B: r = 0.42; p = 0.0112*; C: r = -0.39; p = 0.0213*) and body fat percentage (A: r = 0.83; p < 0.0001*; B: r = 0.58; p = 0.0002*; C: r = -0.64; p < 0.0001*). That is, higher age and body fat were associated with a less brown phenotype prior to cold exposure and with less BAT activity (i.e. lower FF% decline) in response to cold exposure. However, no associations were found between BAT MR outcomes and sex or outdoor temperature. Lastly, liver fat was associated with higher values of pre-cold FF% (r = 0.60; p < 0.0001*) and pre-cold T2* (r = 0.47; p = 0.0040*) while FF% reduction was inversely correlated with liver fat (r = -0.38; p = 0.0295*). Additionally, the relationship between BAT MR outcomes and liver fat still existed after adjusting for age and sex while its effects were mediated by adiposity. CONCLUSION: In this study, a highly reliable MR segmentation protocol was developed that is capable of measuring BAT characteristics and activity irrespective of cold exposure. Additionally, the cold exposure protocol used was sufficient to elicit changes in BAT MR outcomes, as demonstrated by significant changes in FF% and T2* after cooling. Consistent with previous studies, BAT outcomes (as measured by MRI) were associated with age and body fat percentage. Lastly, findings in this thesis provide strong supporting data that BAT may regulate liver lipid content, however, the extent and mechanisms remain to be determined. / Thesis / Master of Science (MSc)

Obesity and insulin resistance are associated with a constellation of features including hypertension, dyslipidaemia, type 2 diabetes, and premature cardiovascular disease, collectively termed the metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic component of this syndrome, incorporating a spectrum of liver disease with increasing morbidity and mortality, from simple steatosis, to non-alcoholic steatohepatitis (or NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. However, factors influencing this progression are incompletely understood. In this thesis I sought to investigate pathways which promote hepatic inflammation and fibrosis by studying two contrasting dietary models of NAFLD in mice in which the risk of hepatic inflammation, insulin resistance and fibrosis differ; namely the methionine and choline deficient diet (MCDD) which induces steatohepatitis, hepatic insulin resistance, and weight loss, and the choline deficient diet (CDD) which may be protected from insulin resistance, and leads to steatosis without inflammation or weight loss. I investigated the possible molecular mechanisms underlying these differences, and whether they influenced progression to hepatic fibrosis induced by carbon tetrachloride (CCl4).