Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal ...studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is strongly increasing and may put patients at increased risk for atherosclerotic cardiovascular disease (asCVD). Both disease phenotypes ...often co-occur, in the case of obesity, insulin resistance, diabetes mellitus type 2, and the metabolic syndrome. We explore the pathogenesis of NAFLD, the epidemiology of asCVD in NAFLD patients, shared drivers of both phenotypes, and factors caused by NAFLD that contribute to asCVD. Genetic studies support that NAFLD may drive asCVD through mixed hyperlipidemia. Next, we discuss the prospects of lifestyle improvement and pharmacological treatment of NAFLD for asCVD risk reduction. Finally, we point out that earlier identification of patients with NAFLD should be pursued by increasing awareness of the association of these two phenotypes and collaboration between the involved physicians.
Non-alcoholic Fatty Liver Disease (NAFLD) and atherosclerotic cardiovascular disease (asCVD) often co-occur.Large epidemiological studies, genetics studies, and studies of subclinical atherosclerosis, support the relation between NAFLD and asCVD.NAFLD–non-alcoholic steatohepatitis (NASH) may directly contribute to asCVD and atherothrombotic events in the hepatic secretion of atherogenic lipoproteins and procoagulant factors.Genetic studies support the relationship between NAFLD and asCVD, notably via increased VLDL secretion. In particular, they support that genetic variants affecting both liver fat and plasma lipid levels have an effect on asCVD risk, while variants with an effect on liver fat only do not affect asCVD.Factors that may drive both NAFLD and asCVD are insulin resistance, hypertension, and potentially chronic periodic hypoxia, as observed in obstructive sleep apnea, and intestinal dysbiosis and chronic low grade inflammation.
Summary
Background
Non‐alcoholic fatty liver disease (NAFLD) has become the most common chronic liver condition. A major current research effort is ongoing to find potential strategies to treat ...NAFLD‐non‐alcoholic steatohepatitis (NASH), with special attention to the gut microbiota. Multiple animal studies and pilot clinical trials are assessing different gut microbiota modulating strategies such as faecal microbiota transplantation, antibiotics, probiotics, prebiotics and synbiotics.
Aim
To review the role of microbiota in NAFLD‐NASH and determine whether pro‐ and prebiotics have potential as treatment
Methods
Information was obtained from critically reviewing literature on PubMed on targeting the gut microbiota in NAFLD. Search terms included NAFLD, NASH, non‐alcoholic fatty liver disease, steatohepatitis; combined with microbiome, microbiota, gut bacteria, probiotics and prebiotics.
Results
Animal studies and the first emerging studies in humans show promising results for both the common probiotics Lactobacillus, Bifidobacterium and Streptococci as for short chain fatty acid (SCFA) butyrate‐producing bacteria. Also, prebiotics have positive effects on different mechanisms underlying NAFLD‐NASH.
Conclusions
The most promising strategies thus far developed to alter the microbiome in NAFLD‐NASH are probiotics and prebiotics. However, pre‐ and probiotic treatment of NAFLD‐NASH is relatively new and still under development. Actual understanding of the involved mechanisms is lacking and changes in the intestinal microbiota composition after treatment are rarely measured. Furthermore, large clinical trials with comparative endpoints are unavailable. Personalised treatment based on metagenomics gut microbiota analysis will probably be part of the future diagnosis and treatment of NAFLD‐NASH.
Abstract
Protein glycosylation is a post-translational modification consisting in the enzymatic attachment of carbohydrate chains to specific residues of the protein sequence. Several types of ...glycosylation have been described, with N-glycosylation and O-glycosylation being the most common types impacting on crucial biological processes, such as protein synthesis, trafficking, localization, and function. Genetic defects in genes involved in protein glycosylation may result in altered production and activity of several proteins, with a broad range of clinical manifestations, including dyslipidaemia and atherosclerosis. A large number of apolipoproteins, lipoprotein receptors, and other proteins involved in lipoprotein metabolism are glycosylated, and alterations in their glycosylation profile are associated with changes in their expression and/or function. Rare genetic diseases and population genetics have provided additional information linking protein glycosylation to the regulation of lipoprotein metabolism.
Background
Exercise is an effective strategy for the prevention and regression of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD), but it is unclear whether it can reduce ...advanced stages of NAFLD, i.e., steatohepatitis and liver fibrosis. Furthermore, it is not evident which modality of exercise is optimal to improve/attenuate NAFLD.
Objectives
The aim is to systematically review evidence for the effect of aerobic exercise (AE) on NAFLD, in particular non-alcoholic steatohepatitis (NASH) and liver fibrosis.
Methods
A systematic literature search was conducted in Medline and Embase. Studies were screened and included according to predefined criteria, data were extracted, and the quality was assessed by Cochrane risk of bias tools by two researchers independently according to the protocol registered in the PROSPERO database (CRD42021270059). Meta-analyses were performed using a bivariate random-effects model when there were at least three randomized intervention studies (RCTs) with similar intervention modalities and outcome.
Results
The systematic review process resulted in an inclusion a total of 24 studies, 18 RCTs and six non-RCTs, encompassing 1014 patients with NAFLD diagnosed by histological or radiological findings. Studies were grouped based on the type of AE: moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). A total of twelve meta-analyses were conducted. Compared to controls, MICT resulted in a mean difference (MD) in the NAFLD biomarkers alanine transaminase (ALT) and aspartate aminotransferase (AST) of -3.59 (CI: -5.60, -1.59, p<0.001) and -4.05 (CI: -6.39, -1.71, p<0.001), respectively. HIIT resulted in a MD of -4.31 (95% CI: -9.03, 0.41, p=0.07) and 1.02 (95% CI: -6.91, 8.94, p=0.8) for ALT and AST, respectively. Moreover, both AE types compared to controls showed a significantly lower magnetic resonance spectroscopy (MRS) determined liver fat with a MD of -5.19 (95% CI: -7.33, -3.04, p<0.001) and -3.41 (95% CI: -4.74, -2.08, p<0.001), for MICT and HIIT respectively. MICT compared to controls resulted in a significantly higher cardiorespiratory fitness (MD: 4.43, 95% CI: 0.31, 8.55, p=0.03).
Conclusion
Liver fat is decreased by AE with a concomitant decrease of liver enzymes. AE improved cardiorespiratory fitness. Further studies are needed to elucidate the impact of different types of AE on hepatic inflammation and fibrosis.
Systematic Review Registration
https://www.crd.york.ac.uk/prospero/
, identifier (CRD42021270059).
Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public ...health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies.
The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS ‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.
Background:
With no approved pharmacotherapy to date, the present therapeutic cornerstone for non-alcoholic fatty liver diseases (NAFLD) is a lifestyle intervention. Guidelines endorse weight loss ...through dietary modifications, physical exercise, or both. However, no consensus exists on the optimal dietary treatment.
Objectives:
The aim of our systematic review and meta-analysis was to summarize and assess the evidence for applied types of dietary interventions on the liver and metabolic outcomes in patients with NAFLD, aside from any effects of exercise intervention.
Methods:
This systematic review was conducted according to the Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) statement guidelines. The search was conducted in PubMed, Scopus, and Cochrane databases in February 2020. Included were only dietary interventions without exercise. This study was registered at PROSPERO: CRD42020203573.
Results:
Eight randomized controlled trials, seven with endpoint reduction of hepatic steatosis, one with an assessment of endpoint fibrosis, were included in this systematic review, five of which were included in the meta-analysis. Mediterranean dietary interventions without energy restriction (
n
= 3) showed significant reduction of intrahepatic lipid content (IHL) (SDM: −0.57, 95% CI: −1.04, −0.10), but there was no significant change in alanine transaminase (ALT) (SDM: 0.59, 95% CI: −0.5, −1.68). Hypocaloric dietary interventions with foods high in unsaturated fatty acids (
n
= 2) led to a significant decrease in ALT (SDM: −1.09, 95% CI: −1.49, −0.69) and aspartate aminotransferase (AST) (SDM: −0.75, 95% CI: −1.27, 0.23); yet effects on steatosis could not be aggregated due to different assessment techniques. Mediterranean diet did not lead to significant changes in concentrations of gamma-glutamyl transpeptidase (γGT), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), fasting glucose or insulin, or homeostatic assessment for insulin resistance.
Conclusions:
In patients with NAFLD, Mediterranean and hypocaloric dietary interventions favoring unsaturated fatty acids result in improvements in IHL and transaminases. Since many dietary intervention studies are combined with exercise interventions and there is a paucity of ample-sized studies examining dietary interventions on the more advanced and clinically relevant stages of NAFLD, that is active and fibrotic NASH, with multiparametric imaging and liver histology as outcome measures, the optimal dietary invention in NAFLD remains to be defined.
There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the ...hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this “HDL hypothesis”. In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct.
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a ...spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased
lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.
In mice, the scavenger receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL ...cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice. It is unclear what role SR-BI plays in human metabolism.
We sequenced the gene encoding SR-BI in persons with elevated HDL cholesterol levels and identified a family with a new missense mutation (P297S). The functional effects of the P297S mutation on HDL binding, cellular cholesterol uptake and efflux, atherosclerosis, platelet function, and adrenal function were studied.
Cholesterol uptake from HDL by primary murine hepatocytes that expressed mutant SR-BI was reduced to half of that of hepatocytes expressing wild-type SR-BI. Carriers of the P297S mutation had increased HDL cholesterol levels (70.4 mg per deciliter 1.8 mmol per liter, vs. 53.4 mg per deciliter 1.4 mmol per liter in noncarriers; P<0.001) and a reduced capacity for efflux of cholesterol from macrophages, but the carotid artery intima-media thickness was similar in carriers and in family noncarriers. Platelets from carriers had increased unesterified cholesterol content and impaired function. In carriers, adrenal steroidogenesis was attenuated, as evidenced by decreased urinary excretion of sterol metabolites, a decreased response to corticotropin stimulation, and symptoms of diminished adrenal function.
We identified a family with a functional mutation in SR-BI. The mutation carriers had increased HDL cholesterol levels and a reduction in cholesterol efflux from macrophages but no significant increase in atherosclerosis. Reduced SR-BI function was associated with altered platelet function and decreased adrenal steroidogenesis. (Funded by the European Community and others.).
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