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The genetics of Non-Alcoholic Fatty Liver Disease: Spotlight on PNPLA3 & TM6SF2 The genetics of Non-Alcoholic Fatty Liver Disease: Spotlight on PNPLA3 & TM6SF2

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Date added: 05/22/2016
Date modified: 05/22/2016
Filesize: 256 Bytes
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Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that spans simple steatosis, through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis. Non-alcoholic fatty liver disease is characterized by substantial inter-patient variation in rate of progression and disease outcome: Although up to 25% of the general population are at risk of progressive disease, only a minority experience associated liver-related morbidity. Non-alcoholic fatty liver disease is considered a complex disease trait that occurs when environmental exposures act upon a susceptible polygenic background composed of multiple independent modifiers. Recent advances include the identification of PNPLA3 as a modifier of disease outcome across the full spectrum of NAFLD from steatosis to advanced fibrosis and hepatocellular carcinoma; and the discovery of TM6SF2 as a potential “master regulator” of metabolic syndrome outcome, determining not only risk of advanced liver disease, but also cardiovascular disease outcomes. In this article, the authors will review the field, discussing in detail the current status of research into these important genetic modifiers of NAFLD progression.

Genome-scale study reveals reduced metabolic adaptability in patients with NAFLD Genome-scale study reveals reduced metabolic adaptability in patients with NAFLD

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Date added: 02/20/2016
Date modified: 11/07/2016
Filesize: 536.46 kB
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Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.

Peripheral Insulin Resistance Predicts Liver Damage in Diabetic Subjects with NAFLD Peripheral Insulin Resistance Predicts Liver Damage in Diabetic Subjects with NAFLD

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Date added: 12/07/2015
Date modified: 11/07/2016
Filesize: 256 Bytes
Downloads: 1495

BACKGROUND & AIMS:

Surrogate indexes of insulin resistance/sensitivity (IR/IS) are widely used in Non Alcoholic Fatty Liver Disease (NAFLD) although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with NAFLD Fibrosis Score (NFS).

METHODS:

Surrogate indexes were validated by tracer technique (D2-glucose and U-13C-glucose) in the basal state and during an Oral Glucose Tolerance Test (OGTT). The best performing indexes were used in an independent cohort of 145 non-diabetic NAFLD subjects to identify liver damage (fibrosis and NASH).

RESULTS:

In the validation NAFLD cohort, HOMA-IR, IGR and ISI Stumvoll had the best association with hepatic IR, while peripheral IS was most significantly related to OGIS, ISI Stumvoll and eMCRnodem . In the independent cohort, only OGTT derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (OR=0.76, 95% CI= 0.61-0.96, P=0.0233) and of NASH (OR=0.75, 95% CI=0.63-0.90, P=0.0021). Both OGIS and NFS identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NFS (OR=0.57, 95% CI=0.45-0.72, P<0.001) and was also able to discriminate F2 from F3/F4 (P<0.003).

CONCLUSIONS:

OGIS is associated with peripheral IS in NAFLD and is inversely associated with an increased risk of significant/advanced liver damage in non-diabetic subjects with NAFLD.

Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism: Implications in NAFLD Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism: Implications in NAFLD

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Date added: 10/11/2015
Date modified: 11/07/2016
Filesize: 2.47 MB
Downloads: 1053

The term non-alcoholic fatty liver disease (NAFLD) covers a pathologic spectrum from lipid accumulation alone (simple steatosis) to steatosis with associated inflammation and fibrosis (non-alcoholic steatohepatitis [NASH]). Non-alcoholic steatohepatitis can progress to cirrhosis and potentially to hepatocellular carcinoma. Although a genetic predisposition has been highlighted, NAFLD is strongly associated with an unhealthy lifestyle and hypercaloric diet in the context of obesity and metabolic disease. The dysregulation of specific pathways (insulin signalling, mitochondrial function, fatty acid, and lipoprotein metabolism) have been linked to steatosis, but elucidating the molecular events determining evolution of the disease still requires further research before it can be translated into specific personalized interventional strategies. In this review, the authors focus on the early events of the pathophysiology of NASH, dissecting the metabolic and nutritional pathways involving fatty acids and glucose sensors that can modulate lipid accumulation in the liver, but also condition the progression to cirrhosis and hepatocellular carcinoma.