Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess ...this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort.
We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies.
Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0–2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression.
Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem, affecting up to a quarter of the world's adult population. The burden of NAFLD is influenced by the ...epidemics of obesity and type 2 diabetes mellitus (T2DM) and the prevalence of these conditions is not expected to decrease in the forthcoming decades. Consequently, the burden of NAFLD-related liver complications (non-alcoholic steatohepatitis NASH, cirrhosis and hepatocellular carcinoma) and the need for life-saving liver transplantation are also expected to increase further in the near future. A large body of clinical evidence indicates that NAFLD is associated not only with increased liver-related morbidity and mortality, but also with an increased risk of developing other important extra-hepatic diseases, such as cardiovascular disease (that is the predominant cause of death in patients with NAFLD), extra-hepatic cancers (mainly colorectal cancers), T2DM and chronic kidney disease. Thus, NAFLD creates a considerable health and economic burden worldwide and often results in poor quality of life. This narrative review provides an overview of the current literature on main complications, morbidity and mortality of this common and burdensome liver disease.
•Clinical burden of NAFLD is not only confined to liver-related mortality and morbidity•NAFLD predicts risk of cardiovascular events•NAFLD predicts risk of chronic kidney disease•NAFLD predicts risk of some extra-hepatic cancers•NAFLD predicts risk of type 2 diabetes mellitus
Metabolic dysfunction associated steatotic liver disease (MASLD) has a strong genetic component. The aim of this study was to examine noninvasively the prevalence of MASLD and of advanced fibrosis in ...relatives of patients with advanced MASLD and the risk factors for liver involvement, with a focus on the contribution of common genetic risk variants.
We prospectively enrolled 98 consecutive probands with advanced fibrosis and/or hepatocellular carcinoma caused by MASLD and 160 nontwin first-degree relatives noninvasively screened for MASLD and advanced fibrosis at 4 Italian centers. We evaluated common genetic determinants and polygenic risk scores of liver disease.
Among relatives, prevalence of MASLD was 56.8% overall, whereas advanced fibrosis was observed in 14.4%. At multivariable analysis in relatives, MASLD was associated with body mass index (odds ratio OR, 1.31 1.18–1.46) and tended to be associated with diabetes (OR, 5.21 0.97–28.10), alcohol intake (OR, 1.32 0.98–1.78), and with female sex (OR, 0.54 0.23–1.15), whereas advanced fibrosis was associated with diabetes (OR, 3.13 1.16–8.45) and nearly with body mass index (OR, 1.09 1.00–1.19). Despite that the PNPLA3 risk variant was enriched in probands (P = .003) and overtransmitted to relatives with MASLD (P = .045), evaluation of genetic risk variants and polygenic risk scores was not useful to guide noninvasive screening of advanced fibrosis in relatives.
We confirmed that about 1 in 7 relatives of patients with advanced MASLD has advanced fibrosis, supporting clinical recommendations to perform family screening in this setting. Genetic risk variants contributed to liver disease within families but did not meaningfully improve fibrosis risk stratification.
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Background/Aims: Immune and inflammatory cells respond to multiple pathological hits in the development of non-alcoholic steatohepatitis (NASH) and fibrosis. Relatively little is known about how ...their type and function change through the non-alcoholic fatty liver disease (NAFLD) spectrum. Here we used multi-dimensional mass cytometry and a tailored bioinformatic approach to study circulating immune cells sampled from healthy individuals and people with NAFLD.
Methods: Cytometry by time of flight using 36 metal-conjugated antibodies was applied to peripheral blood mononuclear cells (PBMCs) from biopsy-proven NASH fibrosis (late disease), steatosis (early disease), and healthy patients. Supervised and unsupervised analyses were used, findings confirmed, and mechanisms assessed using independent healthy and disease PBMC samples.
Results: Of 36 PBMC clusters, 21 changed between controls and disease samples. Significant differences were observed between diseases stages with changes in T cells and myeloid cells throughout disease and B cell changes in late stages. Semi-supervised gating and re-clustering showed that disease stages were associated with fewer monocytes with active signalling and more inactive NK cells; B and T cells bearing activation markers were reduced in late stages, while B cells bearing co-stimulatory molecules were increased. Functionally, disease states were associated with fewer activated mucosal-associated invariant T cells and reduced toll-like receptor-mediated cytokine production in late disease.
Conclusions: A range of innate and adaptive immune changes begin early in NAFLD, and disease stages are associated with a functionally less active phenotype compared to controls. Further study of the immune response in NAFLD spectrum may give insight into mechanisms of disease with potential clinical application. (Clin Mol Hepatol 2023;29:417-432)
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•Dietary fructose causes non-alcoholic liver hepatosis.•Pomegranate alleviates the symptoms of the liver degeneration.•Proteomics revealed mechanisms behind the protection of ...pomegranate.•Bioactives from pomegranate are identified.
Deciphering the mechanisms underlying the direct association between fructose consumption and the onset and progression of non-alcoholic fatty liver disease (NAFLD), as well as the high prevalence of metabolic syndrome (MetS), is of great importance for adopting potential nutritional strategies. Thus, an evaluation of the impact of sustained high fructose consumption on the liver physiology of Wistar rats was made. Moreover, the effectiveness of a dietary pomegranate-derived supplement (P) at counteracting fructose-induced liver injury was also assessed. For unveiling the underlying mechanisms, an untargeted proteomic analysis of the livers from nineteen Wistar rats fed on a basal commercial feed and supplemented with either drinking water (C) (n = 6), 30 % (w/v) fructose in drinking water (F) (n = 7) or 30 % (w/v) fructose solution plus 0.2 % (w/v) P (F+P) (n = 6) was assessed. Fructose intake severely increased the abundance of several energy-production related-proteins, such as fructose-bisphosphate aldolase or fatty acid synthase, among others, as well as diminished the amount of another ones, such as carnitine O-palmitoyl transferase or different subunits of acyl-coenzyme A oxidase. These changes could facilitate mitochondrial disturbances and oxidative stress. Regarding the hepatic proteome of F, P extract restored mitochondrial homeostasis and strengthened endogenous antioxidant mechanisms diminishing the amount of proteins involved in process that could increase the oxidative status, as well as increasing both the quantity of several proteins involved in proteasome functionality, as expressing changes in the amount of certain RNA-splicing related-proteins, regarding F proteome.
ABSTRACT
Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl‐CoA subunits that are produced from a number of different pathways within the cell, most ...commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non‐alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance.
Nonalcoholic fatty liver disease (NAFLD) refers to the uncontrolled accumulation of triglyceride (TG) in the liver when the person has no other liver disease etiologies. Among all causes of ...neuropathy, diabetic neuropathy is the most common one worldwide, and it causes notable morbidity and increases mortality. The prevalence of diabetic neuropathy and NAFLD has been demonstrated in few studies. This study aims to summarize existing data estimating peripheral diabetic neuropathy prevalence among sonographically detected NAFLD patients. We searched PubMed, Scopus, Web of Science, and Google scholar for articles in the English language up until October 2021 for the clinical trials of diabetic neuropathy in NAFLD patients and used the articles for a systematic review and meta-analysis. Seven studies (6,918 patients with type 2 diabetes mellitus (T2DM)) were involved. The prevalence of diabetic neuropathy among T2DM patients with ultrasound (US) detected-NAFLD was 0.48 (95% CI= 0.31-0.65, I2= 99.01%), however it was not significantly different from patients without NAFLD (OR=1.02, 95% CI= 0.89-1.17. p=0.748, I2=81.6%). The prevalence of diabetic neuropathy among T2DM patients with NAFLD is not significantly different from patients without NAFLD.
Recent studies examined the prognostic impact of nonalcoholic fatty liver disease (NAFLD) on the risk of incident chronic kidney disease (CKD). However, the extent to which NAFLD may confer risk of ...incident CKD is uncertain. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident CKD.
We searched PubMed, Scopus and Web of Science from January 1, 2000 to August 31, 2017 using pre-defined keywords to identify large observational cohort studies with a follow-up duration of at least 1year, in which NAFLD was diagnosed by biochemistry, fatty liver index or ultrasonography. No studies with biopsy-proven NAFLD were available for the analysis. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling.
A total of 9 observational studies with 96,595 adult individuals (34.1% with NAFLD) of predominantly Asian descent, and 4653 cases of incident CKD stage ≥3 (i.e., defined as occurrence of estimated glomerular filtration rate<60ml/min/1.73m2, with or without accompanying overt proteinuria) over a median period of 5.2years were included in the final analysis. Patients with NAFLD had a significantly higher risk of incident CKD than those without NAFLD (random-effects hazard ratio HR 1.37, 95% CI 1.20–1.53; I2=33.5%). Patients with more ‘severe’ NAFLD (according to ultrasonography and non-invasive fibrosis markers) were also more likely to develop incident CKD (n=2 studies; random-effects HR 1.50, 95% CI 1.25–1.74; I2=0%); this risk appeared to be even greater among those with ultrasound-diagnosed NAFLD and a high-intermediate NAFLD fibrosis score (n=1 study; random-effects HR 1.59, 95% CI 1.31–1.93). Sensitivity analyses did not alter these findings. Funnel plot and Egger's test did not reveal significant publication bias.
This largest and most updated meta-analysis to date shows that NAFLD (detected by biochemistry, fatty liver index or ultrasonography) is associated with a nearly 40% increase in the long-term risk of incident CKD. However, the observational nature of the eligible studies does not allow for proving causality. Our findings pave the way for future large, prospective, histologically-based studies.
Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been ...considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD.
MAFLD: How is it different from NAFLD? Gofton, Cameron; Upendran, Yadhavan; Zheng, Ming-Hua ...
Clinical and molecular hepatology,
02/2023, Volume:
29, Issue:
Suppl
Journal Article
Peer reviewed
Open access
"Metabolic dysfunction-associated fatty liver disease (MAFLD)" is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from ...nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.
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