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


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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    • "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]. "

    Journal of Hepatology 10/2015; DOI:10.1016/j.jhep.2015.09.023 · 11.34 Impact Factor
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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.
    Biochimica et Biophysica Acta 08/2015; 1852(11). DOI:10.1016/j.bbadis.2015.08.022 · 4.66 Impact Factor
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    • "Hepatic steatosis can progress to nonalcoholic steatohepatitis (NASH), which is distinguished from simple steatosis by the presence of hepatocyte ballooning, inflammation, and fibrosis. NASH can progress to cirrhosis [3]. The prevalence of NAFLD varies according to the diagnostic tools and study population. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue can lead to NAFLD related with insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is one of the phenotypes of insulin resistance or metabolic syndrome. Many researchers have discovered a close association between NAFLD and insulin resistance, and focused on the role of NAFLD in the development of type 2 diabetes. Further, substantial evidence has suggested the association between NAFLD and cardiovascular disease (CVD). In the current review, we provide a plausible mechanistic link between NAFLD and CVD and the potential of the former as a therapeutic target based on pathophysiology. We also discuss in detail about the role of insulin resistance, oxidative stress, low-grade inflammation, abnormal lipid metabolism, gut microbiota, changes of biomarkers, and genetic predisposition in the pathological linking between NAFLD and cardiometabolic disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 08/2015; 201:408-414. DOI:10.1016/j.ijcard.2015.08.107 · 4.04 Impact Factor
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