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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: 737

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.

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
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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.

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.

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.

Genetics of alcoholic liver disease Genetics of alcoholic liver disease

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Date added: 05/22/2016
Date modified: 05/22/2016
Filesize: 256 Bytes
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Excess alcohol consumption with consequent alcoholic liver disease (ALD) is a common cause of liver dysfunction and liver-related mortality worldwide. However, although the majority of heavy drinkers will develop steatosis, only a minority progress to advanced liver disease and cirrhosis. Thus, ALD is a complex disease where subtle inter-patient genetic variations and environmental factors interact to determine disease progression. One genome-wide association study specifically addressing genetic modifiers of ALD has been published. However, most of our understanding is based on studies conducted on nonalcoholic fatty liver disease. Translation of candidates from these studies into ALD has established a role for variants in genes including PNPLA3 and potentially TM6SF2 across the disease spectrum from steatosis, through cirrhosis to hepatocellular carcinoma. Here the authors review the current status of the field with a particular focus on recent advances.

Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in NAFLD Plasma DNA methylation: A potential biomarker for stratification of liver fibrosis in NAFLD

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Date added: 05/22/2016
Date modified: 09/27/2016
Filesize: 2.77 MB
Downloads: 530

Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD.

Non-alcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum Non-alcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum

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Date added: 05/22/2016
Date modified: 05/22/2016
Filesize: 256 Bytes
Downloads: 875

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered.

Fibrogenesis assessed by serological type III collagen formation identifies patients with progressiv Fibrogenesis assessed by serological type III collagen formation identifies patients with progressiv

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Date added: 11/07/2016
Date modified: 11/07/2016
Filesize: 256 Bytes
Downloads: 709

Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis and can potentially identify patients most likely to benefit from anti-metabolic and potential anti-fibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up anti-fibrotic drug development and validation.

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

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Date added: 01/09/2017
Date modified: 01/10/2017
Filesize: 1.02 MB
Downloads: 305

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

Phosphorylated IGFBP-1 as a non-invasive predictor of liver fat in NAFLD Phosphorylated IGFBP-1 as a non-invasive predictor of liver fat in NAFLD

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Date added: 01/10/2017
Date modified: 01/10/2017
Filesize: 505.25 kB
Downloads: 337

Insulin-like growth factor binding protein 1 (IGFBP-1) is a potentially interesting marker for liver fat in NAFLD as it is exclusively produced by the liver, and insulin is its main regulator. We determined whether measurement of fasting serum phosphorylated IGFBP-1 (fS-pIGFBP-1) helps to predict liver fat compared to routinely available clinical parameters and PNPLA3 genotype at rs738409. Liver fat content (proton magnetic resonance spectroscopy) was measured in 378 subjects (62% women, age 43 [30–54] years, BMI 32.7 [28.1–39.7] kg/m2, 46% with NAFLD). Subjects were randomized to discovery and validation groups, which were matched for clinical and biochemical parameters and PNPLA3 genotype. Multiple linear regression and Random Forest modeling were used to identify predictors of liver fat. The final model, % Liver Fat Equation’, included age, fS-pIGFBP-1, S-ALT, waist-to-hip ratio, fP-Glucose and fS-Insulin (adjusted R2 = 0.44 in the discovery group, 0.49 in the validation group, 0.47 in all subjects). The model was significantly better than a model without fS-pIGFBP-1 or S-ALT or S-AST alone. Random Forest modeling identified fS-p-IGFBP-1 as one of the top five predictors of liver fat (adjusted R2 = 0.39). Therefore, measurement of fS-pIGFBP-1 may help in non-invasive prediction of liver fat content.