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Human Fatty Liver Disease: Old Questions and New Insights

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Science (Impact Factor: 31.48). 06/2011; 332(6037):1519-23. DOI: 10.1126/science.1204265
Source: PubMed

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing
number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver,
which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD
is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options
are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human
genetic and metabolic studies.

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    • "Triglycerides (TG) accumulation is an efficient energy storage mechanism. When compared to carbohydrates (4,5 kcal/g) or proteins (4 kcal/g), TG provides higher caloric intake (9 kcal/g) [9]. As so, it is advantageous for the organism to convert carbohydrates and amino acids into TG to be stored in adipose tissue, in order to be used in times of fasting or prolonged exercise [10]. "
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    DESCRIPTION: Nádia Duarte,1,2 Inês C. Coelho,1,2 Rita S. Patarrão,1,2 Joana I. Almeida,2 Carlos Penha-Gonçalves,2,3 andM. Paula Macedo1,3
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    • "NAFLD is a common and genetically complex disorder with an estimated heritability of 39% (Schwimmer et al. 2009). Several candidate genes studies and three genomewide association studies (GWAS) have been performed to identify the associated genes for NAFLD (Cohen et al. 2011; Hernaez 2011). There is evidence that while disease associated with single-nucleotide polymorphisms (SNPs) are not significantly more differentiated between populations than random SNPs in the genome on average, risk allele frequencies do show substantial variation across human populations and may account for differences in disease "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a distinct pathologic condition characterized by a disease spectrum ranging from simple steatosis to steato-hepatitis, cirrhosis and hepatocellular carcinoma. Prevalence of NAFLD varies in different ethnic groups, ranging from 12% in Chinese to 45% in Hispanics. Among Indian populations, the diversity in prevalence is high, ranging from 9% in rural populations to 32% in urban populations, with geographic differences as well. Here, we wished to find out if this difference is reflected in their genetic makeup. To date, several candidate genes and a few genomewide association studies (GWAS) have been carried out, and many associations between single nucleotide polymorphisms (SNPs) and NAFLD have been observed. In this study, the risk allele frequencies (RAFs) of NAFLD-associated SNPs in 20 Indian ethnic populations (376 individuals) were analysed. We used two different measures for calculating genetic risk scores and compared their performance. The correlation of additive risk scores of NAFLD for three Hapmap populations with their weighted mean prevalence was found to be high (R 2=0.93). Later we used this method to compare NAFLD risk among ethnic Indian populations. Based on our observation, the Indian caste populations have high risk scores compared to Caucasians, who are often used as surrogate and similar to Indian caste population in disease gene association studies, and is significantly higher than the Indian tribal populations.
    Journal of Genetics 03/2015; 94(1). DOI:10.1007/s12041-015-0494-0 · 1.01 Impact Factor
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    • "The histopathological spectrum of NAFLD covers excess fat deposition within hepatocytes (simple steatosis), as well as steatosis with inflammation and fibrosis (nonalcoholic steatohepatitis , NASH) which can lead to cirrhosis and to hepatocellular carcinoma [2]. The lipid storage within the hepatocytes is a cause of cell enlargements that could impair hepatic microcirculation, oxygen delivery and mitochondrial function [3] [4]. "
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    ABSTRACT: There is an unmet medical need for novel NAFLD treatments. Here we have examined the effects of liver-selective NO donor (V-PYRRO/NO) as compared with metformin on hepatic steatosis and glucose tolerance in mice fed high fat diet. Effects of V-PYRRO/NO (5mgkg(-1)) or metformin (616mgkg(-1)) were examined in C57BL/6J mice fed high fat diet (HF, 60 kcal% fat). Quantitative determination of steatosis, liver fatty acid composition and western blot analysis of selected proteins involved in mitochondrial biogenesis, fatty acid de novo synthesis and oxidation, triacylglycerols and cholesterol transport from the liver were performed. Liver NOx and nitrate concentration and blood biochemistry were also analyzed. V-PYRRO/NO and metformin reduced liver steatosis with simultaneous reduction of total liver triacylglycerols, diacylglycerols and ceramides fraction and reversed HF-induced decrease in UFA/SFA ratio. V-PYRRO/NO substantially improved postprandial glucose tolerance, while the effect of metformin was modest and more pronounced on HOMA IR index. The anti-steatotic mechanism of V-PYRRO/NO was dependent on NO release, differed from that of metformin and involved improved glucose tolerance and inhibition of de novo fatty acid synthesis by Akt activation and ACC phosphorylation. In turn, major mechanism of metformin action involved increased expression of proteins implicated in mitochondrial biogenesis and metabolism (PGC-1α, PPARα, COX IV, cytochrome c, HADHSC). V-PYRRO/NO acts as a liver-specific NO donor pro-drug affording pronounced anti-steatotic effects and may represent an efficient, mechanistically novel approach to prevent liver steatosis and insulin resistance. Copyright © 2014. Published by Elsevier Inc.
    Biochemical Pharmacology 12/2014; 93(3). DOI:10.1016/j.bcp.2014.12.004 · 4.65 Impact Factor
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