715 research outputs found
Lipid droplets in steatotic liver disease
No full textPurpose of review: this review aims to discuss the most recent evidence exploring the role of lipid droplets in steatotic liver disease (SLD). We highlight the breadth of mechanisms by which lipid droplets may contribute to the progression of SLD with a particular focus on the role of lipid droplets as inducers of mechanical stress within hepatocytes and genetic mutations in lipid droplet associated proteins. Finally, this review provides an update on clinical trials exploring the therapeutic potential and strategies targeting lipid droplets.Recent findings: the size, composition and location of hepatic lipid droplets strongly influence the pathological role of these organelles in SLD. Emerging studies are beginning to elucidate the importance of lipid droplet induced hepatocyte mechanical stress. Novel strategies targeting lipid droplets, including the effects of lipid droplet associated protein mutations, show promising therapeutic potential.Summary: much more than a histological feature, lipid droplets are complex heterogenous organelles crucial to cellular metabolism with important causative roles in the development and progression of SLD. Lipid droplet induced mechanical stress may exacerbate hepatic inflammation and fibrogenesis and potentially contribute to the development of a pro-carcinogenic hepatic environment. The integration of advancements in genetics and molecular biology in upcoming treatments aspires to transcend symptomatic alleviation and address the fundamental causes and pathological development of SLD
Extrahepatic diseases and NAFLD: The triangular relationship between NAFLD, type 2-diabetes and dysbiosis
No full textEffect of omega-3 fatty acids in non-alcoholic fatty liver disease
No full textThe first chapter (Introduction) of the thesis summarises the pathogenesis of NAFLD and its associated risk factors such as type 2 diabetes and cardiovascular disease. Moreover, it describes: a) the potential beneficial effects of long chain omega-3 fatty acid treatment [docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA)] in NAFLD; b) the effect of genotypes patatin-like phospholipase domain-containing protein-3 (PNPLA3 I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2 E167K), on the level of DHA and EPA enrichment and end of study liver fat percentage after DHA+EPA treatment; and c) the effect of fatty acid desaturase (FADS) and Elongase (ELOVL) polymorphisms influencing omega-3 fatty acid metabolism. The second chapter describes the overall aim of this thesis. The aim of my research was to investigate in patients with NAFLD: a) the effect of long-chain omega-3 fatty acid treatment on liver fat percentage and liver fibrosis biomarkers; b) the effect of genotypes influencing NAFLD severity on treatment with DHA+EPA; and c) the effect of genotypes influencing omega-3 fatty acid metabolism in NAFLD. The third chapter describes in details the design and methods used in my research. Chapter four highlights my novel results from the WELCOME study. This chapter describes the baseline and end of study characteristics of the WELCOME study participants and shows the results of the DHA+EPA treatment on liver fat percentage and liver fibrosis biomarkers. This chapter also describes the association between DHA erythrocyte enrichment and decrease in liver fat percentage after DHA+EPA treatment. Chapter five illustrates the association between PNPLA3 I148M and DHA erythrocyte enrichment percentage and end of study liver fat percentage after DHA+EPA treatment. The chapter shows that PNPLA3 I148M was associated with higher end of study liver fat percentage and lower DHA tissue enrichment. Chapter six shows the negative association between FADS polymorphisms and omega-3 fatty acid metabolism in NAFLD. The chapter also shows that there was a gene-DHA+EPA interaction between the minor allele of the FADS1 rs174556 and Δ-5 desaturase activity after treatment with DHA+EPA. Finally, chapter seven, summarises my results in the context of current evidence and knowledge about the subject matter
Omega-3 fatty acids and non-alcoholic fatty liver disease: evidence of efficacy and mechanism of action
No full textFor many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised trials in both adults and children with NAFLD; and finally to discuss key ‘known unknowns’ that need to be considered, before planning future studies that are focussed on testing the effects of omega-3 fatty acid treatment in patients with NAFLD
Nonalcoholic Fatty Liver Disease and Reduced Serum Vitamin D3 levels
No full textAbstract Nonalcoholic fatty liver disease (NAFLD) and vitamin D3 deficiency are two highly prevalent pathologic conditions worldwide that share several cardiometabolic risk factors. In addition to its traditional calcium-related effects on the skeleton, vitamin D3 deficiency has now been recognized to exert nonskeletal adverse effects on several other organ systems. Accumulating epidemiological evidence suggests that low levels of serum 25-hydroxyvitamin D3 are associated with the presence and severity of NAFLD, independently of several potential confounders, including features of the metabolic syndrome. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a hepato-protective role for the active metabolite of vitamin D3. 1?,25-dihydroxyvitamin D3 modulates the insulin signaling pathway/insulin resistance, suppresses fibroblast proliferation and collagen production, exerts anticoagulant and profibrinolytic effects, and modulates macrophage activity and inflammatory cytokine generation. Overall, the high prevalence of vitamin D3 deficiency and the plausible biological mechanisms linking this to NAFLD suggest that treatment of vitamin D3 deficiency to prevent and/or treat NAFLD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D3 supplementation could have any potential benefit in reducing the development and progression of NAFLD
Bile acids as emerging players at the intersection of steatotic liver disease and cardiovascular diseases
No full textAffecting approximately 25% of the global population, steatotic liver disease (SLD) poses a significant health concern. SLD ranges from simple steatosis to metabolic dysfunction-associated steatohepatitis and fibrosis with a risk of severe liver complications such as cirrhosis and hepatocellular carcinoma. SLD is associated with obesity, atherogenic dyslipidaemia, and insulin resistance, increasing cardiovascular risks. As such, identifying SLD is vital for cardiovascular disease (CVD) prevention and treatment. Bile acids (BAs) have critical roles in lipid digestion and are signalling molecules regulating glucose and lipid metabolism and influencing gut microbiota balance. BAs have been identified as critical mediators in cardiovascular health, influencing vascular tone, cholesterol homeostasis, and inflammatory responses. The cardio-protective or harmful effects of BAs depend on their concentration and composition in circulation. The effects of certain BAs occur through the activation of a group of receptors, which reduce atherosclerosis and modulate cardiac functions. Thus, manipulating BA receptors could offer new avenues for treating not only liver diseases but also CVDs linked to metabolic dysfunctions. In conclusion, this review discusses the intricate interplay between BAs, metabolic pathways, and hepatic and extrahepatic diseases. We also highlight the necessity for further research to improve our understanding of how modifying BA characteristics affects or ameliorates disease
Factors independently associated with cardiorespiratory fitness in patients with non-alcoholic fatty liver disease
No full textLow cardiorespiratory fitness (CRF) is associated with non-alcoholic fatty liver disease (NAFLD) and low CRF is an important risk factor for cardiovascular disease. The factors that influence CRF in NAFLD are poorly understood and it has been suggested that reduced hepatic mitochondrial function (HMF) may be linked to low CRF. Therefore, our aim was to determine the factors associated with CRF in NAFLD.METHODS: Ninety-seven patients with NAFLD were studied. CRF was assessed by treadmill testing and expressed as maximal O
2 consumption (VO
2 peak) per lean body mass. HMF was assessed by the
13 C-ketoisocaproate breath test. Multivariable linear regression modelling was undertaken to test the independence of associations with CRF.
RESULTS: Mean (SD) age was 51 (13) years and 61% were men. With CRF as the outcome, age (B coefficient -0.3, 95%CI -0.4, -0.2, P < .0001), total body fat mass (B coefficient -0.2, 95%CI -0.3, -0.05, P = .01), type 2 diabetes mellitus (T2DM) (B coefficient -3.6, 95%CI -1.1, -6.1, P = .005), smoking status (B coefficient -5.7, 95%CI -1.9, -9.5, P = .004), serum γ-glutamyl transferase (GGT) (B coefficient -0.04, 95%CI -0.05, -0.02, P < .0001), HMF (B coefficient -0.5, 95%CI -0.8, -0.1, P = .01) and diastolic function (B coefficient 0.1, 95%CI 0.05, 0.13, P < .0001) were independently associated with CRF. This model explained 60% of the total variance in CRF (R
2 = 0.6, P < .0001); and this model with GGT alone explained 24% of the variance in CRF.
CONCLUSIONS: In patients with NAFLD, HMF is independently associated with CRF and a model with GGT alone explained most of the variance in CRF.</p
Diagnosis and management of non-alcoholic fatty liver disease
No full textNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western industrialised countries. The prevalence of NAFLD is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. NAFLD represents a spectrum of liver disease severity. NAFLD begins with accumulation of triacylglycerols in the liver (steatosis), and is defined by hepatic fatty infiltration amounting to greater than 5% by liver weight or the presence of over 5% of hepatocytes loaded with large fat vacuoles. In almost a quarter of affected individuals, steatosis progresses with the development of liver inflammation to non-alcoholic steatohepatitis (NASH). NASH is a potentially progressive liver condition and with ongoing liver injury and cell death can result in fibrosis. Progressive liver fibrosis may lead to the development of cirrhosis in a small proportion of patients. With the growing prevalence of NAFLD, there is an increasing need for a robust, accurate and non-invasive approach to diagnosing the different stages of this condition. This review will focus on (1) the biochemical tests and imaging techniques used to diagnose the different stages of NAFLD; and (2) a selection of the current management approaches focusing on lifestyle interventions and pharmacological therapies for NAFLD
The evaluation of the repeatability of the 13C-ketoisocaproate breath test for assessing hepatic mitochondrial function
No full textThe 13C-ketoisocaproate (13C-KICA) breath test (BT) has been recently proposed as a non-invasive test for assessing hepatic mitochondrial function. Results of the 13C-KICA BT can be expressed as different parameters. However, the best parameter for expressing the 13C-KICA BT result is uncertain which hinders use of the BT in routine clinical practice. We have investigated the repeatability of different parameters of 13C-KICA BT. Thirteen healthy adult subjects (5 men and 8 women) underwent a 13C-KICA BT on two occasions separated by a gap of approximately 30 days. There were no significant differences between the repeated measurements for all the test parameters over 30 days. Furthermore, the Bland Altman statistics showed no fixed or proportional bias for any of the test parameters. The cumulative 13C-dose enrichment over 60 min had the lowest within-subject variability of 12% compared to all other test parameters. The cumulative 13C-dose enrichment over 60 min could be a very useful parameter for the 13C-KICA BT to detect impaired hepatic mitochondrial function in patients with chronic liver diseases
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