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 P465L pparγ mutation confers partial resistance to the hypolipidemic action of fibrates P465L pparγ mutation confers partial resistance to the hypolipidemic action of fibrates

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Date added: 06/30/2019
Date modified: 06/30/2019
Filesize: 1.63 MB
Downloads: 144

Aims
Familial partial lipodystrophic syndrome 3 (FPLD3) is associated with mutations in the transcription factor PPARγ. One of these mutations, the P467L, confers a dominant negative effect. We and others have previously investigated the pathophysiology associated with this mutation using a humanized mouse model that recapitulates most of the clinical symptoms observed in patients who have been phenotyped under different experimental conditions. One of the key clinical manifestations observed, both in humans and mouse models, is the ectopic accumulation of fat in the liver. With this study we aim to dissect the molecular mechanisms that contribute to the excessive accumulation of lipids in the liver and characterize the negative effect of this PPARγ mutation on the activity of PPARα in vivo when activated by fibrates.

Material and Methods
P465L‐PPAR mutant and wild‐type mice were divided into 8 experimental groups, 4 different conditions per genotype. Briefly, mice were fed a chow diet or a high‐fat diet (HFD 45% Kcal from fat) for a period of 28 days and treated with WY14643 or vehicle for five days before culling. At the end of the experiment, tissues and plasma were collected. We performed extensive gene expression, fatty acid composition and histological analysis in the livers. The serum collected was used to measure several metabolites and to perform basic lipoprotein profile.

Results
P465L mice showed increased levels of insulin and free fatty acids (FFA) as well as increased liver steatosis. They also exhibit decreased levels of very low density lipoproteins (VLDL) when fed an HFD. We also provide evidence of impaired expression of a number of well‐established PPARα target genes in the P465L mutant livers.

Conclusion
Our data demonstrate that P465L confers partial resistance to the hypolipidemic action of fibrates. These results show that the fatty liver phenotype observed in P465L mutant mice is not only the consequence of dysfunctional adipose tissue, but also involves defective liver metabolism. All in all, the deleterious effects of P465L‐PPARγ mutation may be magnified by their collateral negative effect on PPARα function.

A spotlight on pathogenesis, interactions and novel therapeutic options in NAFLD A spotlight on pathogenesis, interactions and novel therapeutic options in NAFLD

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Date added: 07/29/2019
Date modified: 07/29/2019
Filesize: 256 Bytes
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In 2018, there have been substantial advances in our understanding of the risk factors for advanced liver disease in nonalcoholic fatty liver disease, including genetic variants and the gut microbiota. Promising results have also arisen from drugs targeting metabolic pathways involved in the progression of liver damage.

Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis

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Date added: 08/22/2017
Date modified: 08/22/2017
Filesize: 338.38 kB
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OBJECTIVES: Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD.

METHODS: Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36–45 (n=96), 46–55 (n=197), 56–64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3–F4) for each group was assessed using liver biopsy as the standard.

RESULTS: Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77–0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%).

CONCLUSIONS: The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

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Date added: 11/01/2018
Date modified: 11/01/2018
Filesize: 256 Bytes
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Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography–mass
spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR 5 endogenous glucose production 3 insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine 1 glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R 5 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort.

Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index.

Assessment of Liver Fibrosis Progression and Regression by a Serological Collagen Turnover Profile Assessment of Liver Fibrosis Progression and Regression by a Serological Collagen Turnover Profile

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Date added: 07/29/2019
Date modified: 07/29/2019
Filesize: 256 Bytes
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There is a need for noninvasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to antifibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be included in clinical studies with fibrosis as end point. Circulating biomarkers, originating from defined fragments of the scar tissue itself, may serve as valuable tools for this aspect of precision medicine. We investigated a panel of serological collagen formation and degradation markers to identify patients likely to regress or progress in absence of a therapeutic intervention. Plasma samples from patients with moderate-stage hepatitis C receiving placebo treatment in a phase II trial of the peroxisome proliferator-activated receptor agonist farglitazar were included. The patients had matched liver biopsies at baseline and 52 wk of follow-up. Serological biomarkers of collagen formation (PRO-C3, PRO-C4, PRO-C5) and collagen degradation (C3M, C4M, and C6M) were analyzed. Logistic regression analysis including PRO-C3 and C6M identified subjects with progressive liver fibrosis with an AUROC of 0.91 (P < 0.0001) and positive and negative predictive values (PPV/NPV) of 75.0%/88.6%. Low levels of PRO-C5 predicted a spontaneous regression phenotype, with an odds ratio of 33.8 times higher compared with patients with high levels (P < 0.0025) with an AUROC of 0.78 (P < 0.0001) and PPV/NPV of 60.0%/95.7%. Two collagen fragments (PRO-C3 and C6M) identified liver fibrosis progressors, and one collagen fragment (PRO-C5) identified liver fibrosis regressors. These biomarkers may improve patient stratification and monitor treatment efficacy in studies with fibrosis as clinical end point.

In this study we report two biomarkers of collagen fragments (PRO-C3 and C6M) that are able to identify liver fibrosis progressors while one biomarker (PRO-C5) identified liver fibrosis regressors. In particular, we present three noninvasive biomarkers that can be used to identify patients with progressive liver fibrosis, monitor response to antifibrotic therapy, and also identify the spontaneous liver fibrosis regression phenotype.

Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic

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Date added: 01/10/2017
Date modified: 01/10/2017
Filesize: 661.91 kB
Downloads: 908

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and fibrosis. “Obese/Metabolic NAFLD” is closely associated with obesity and insulin resistance and therefore predisposes to type 2 diabetes and cardiovascular disease. NAFLD can also be caused by common genetic variants, the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2). Since NAFL, irrespective of its cause, can progress to NASH and liver fibrosis, its definition is of interest. We reviewed the literature to identify data on definition of normal liver fat using liver histology and different imaging tools, and analyzed whether NAFLD caused by the gene variants is associated with insulin resistance. Histologically, normal liver fat content in liver biopsies is most commonly defined as macroscopic steatosis in less than 5% of hepatocytes. In the population-based Dallas Heart Study, the upper 95th percentile of liver fat measured by proton magnetic spectroscopy (1H-MRS) in healthy subjects was 5.6%, which corresponds to approximately 15% histological liver fat. When measured by magnetic resonance imaging (MRI)-based techniques such as the proton density fat fraction (PDFF), 5% macroscopic steatosis corresponds to a PDFF of 6% to 6.4%. In contrast to “Obese/metabolic NAFLD”, NAFLD caused by genetic variants is not associated with insulin resistance. This implies that NAFLD is heterogeneous and that “Obese/Metabolic NAFLD” but not NAFLD due to the PNPLA3 or TM6SF2 genetic variants predisposes to type 2 diabetes and cardiovascular disease.

Determinants of fibrosis progression and regression in NASH Determinants of fibrosis progression and regression in NASH

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Date added: 11/02/2018
Date modified: 11/02/2018
Filesize: 256 Bytes
Downloads: 454

Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-ofconcept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.

Emerging anti-fibrotic therapies in the treatment of non-alcoholic steatohepatitis Emerging anti-fibrotic therapies in the treatment of non-alcoholic steatohepatitis

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Date added: 03/05/2017
Date modified: 03/05/2017
Filesize: 256 Bytes
Downloads: 1501

Background

Non-alcoholic fatty liver disease (NAFLD) can lead to non-alcoholic steatohepatitis (NASH) and cirrhosis. Fibrosis predicts worse outcomes and mortality. New treatments targeting fibrosis are being investigated to reverse disease progression.

Aim

To review the new pipeline therapeutic agents targeting fibrosis in NASH patients, with particular focus on clinical trials in which reversing fibrosis and portal hypertension are the primary outcomes.

Methods

The literature was searched in PubMed between January 2000 and January 2016 using search terms non-alcoholic fatty liver disease and NASH, with filters of ‘English language’. We focused on fibrosis improvement as the key outcome. We also searched the ClinicalTrials.gov for promising agents that target fibrosis in NASH patients.

Results

Significant advances have been made on approaches targeting fibrosis in NASH patients. Many therapeutic agents are already in development, some of which have shown promising results in preclinical and phase I studies. Novel therapies have entered phase II and III studies targeting fibrosis reversal and/or improvement in portal hypertension. Innovative studies have also started looking into combining these agents, aiming at different mechanisms to maximise therapeutic outcomes. We found five clinical trials in phase II and one in phase III focusing on fibrosis in NASH patients as key outcomes. One of the phase II trials is using combination therapy to target fibrosis.

Conclusions

Ongoing research studies are already investigating new pathways aimed at reversing fibrosis in NASH patients. Novel therapeutic agents are in development and are expected to offer unique options to NASH patients with advanced fibrosis.

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: 2210

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.

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: 1606

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.