Article

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: 33.61). 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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    • "In general, NAFLD is closely linked with overnutrition , visceral fat accumulation, and obesity. Nonalcoholic steatohepatitis (NASH) is a serious subtype of NAFLD that may progress to cirrhosis, hepatocellular carcinoma, and hepatic failure [1] [2] [3]. Therefore, understanding the pathogenesis of NASH is important for the development of proper preventive and therapeutic strategies. "

    Full-text · Dataset · Jan 2016
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    • "Following the trail of the obesity epidemics, Non-alcoholic fatty liver disease (NAFLD), defined by hepatic triglycerides content exceeding 5% in the absence of at risk alcohol intake [1], has become the leading cause of liver disease [2] [3]. This condition is epidemiologically associated with metabolic syndrome and insulin resistance, that increases the hepatic flux of free fatty acids from adipose tissue, and leads to de novo lipogenesis [4] [5] [6]. NAFLD encompasses a spectrum of conditions ranging from simple steatosis, usually a non-progressive condition, to Non-alcoholic steatohepatitis (NASH), characterized by hepatocellular damage, lobular necroinflammation, and fibrogenesis [7] [8]. "

    Full-text · Article · Oct 2015 · Journal of Hepatology
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    • "Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease associated with metabolic syndrome in civilized countries [1] [2] [3]. Although steatosis caused by the accumulation of triglyceride (TG) in liver is a benign clinical course, it can progress to non-alcoholic steatohepatitis (NASH) characterized by hepatic injury, inflammation and fibrosis, and eventually advance to cirrhosis and hepatocellular carcinoma [1] [2] [3]. Nevertheless, the pathological mechanisms underlying NASH are not completely understood. "
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    ABSTRACT: Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). TRC8 is an ER-resident E3 ligase with roles in modulating lipid and protein biosynthesis. In this study we showed that TRC8 expression was downregulated in steatotic livers of patients and mice fed with high fat diet (HFD) or methionine and choline deficient (MCD) diet. To investigate the impact of TRC8 downregulation on steatosis and the progression to non-alcoholic steatohepatitis (NASH), we placed TRC8 knockout (KO) mice and wild type (WT) controls on HFD or MCD diet and the severities of steatosis and NASH developed were compared. We found that TRC8 deficiency did not significantly affect diet-induced steatosis. Nevertheless, MCD diet-induced NASH as characterized by hepatocyte death, inflammation and fibrosis were exacerbated in TRC8-KO mice. The hepatic ER stress response, as evidenced by increased eIF2α phosphorylation and expression of ATF4 and CHOP, and the level of activated caspase 3, an apoptosis indicator, were augmented by TRC8 deficiency. The hepatic ER stress and NASH induced in mice could be ameliorated by adenovirus-mediated hepatic TRC8 overexpression. Mechanistically, we found that TRC8 deficiency augmented lipotoxic-stress-induced unfolded protein response in hepatocytes by attenuating the arrest of protein translation and the misfolded protein degradation. These findings disclose a crucial role of TRC8 in the maintenance of ER protein homeostasis and its downregulation in steatotic liver contributes to the progression of NAFLD. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · Biochimica et Biophysica Acta
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