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1.
Role of the mTOR-autophagy-ER stress pathway in high fructose-induced metabolic-associated fatty liver disease.
Wang, YL, Zhou, X, Li, DL, Ye, JM
Acta pharmacologica Sinica. 2022;(1):10-14
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Abstract
Metabolic-associated fatty liver disease (MAFLD) is the most common metabolic disease with a global prevalence of 25%. While MAFLD is serious and incurable at the later stage, it can be controlled or reversed at the early stage of hepatosteatosis originating from unhealthy diets. Recent laboratory evidence implicates a critical role of the mammalian target of rapamycin (mTOR)-autophagy signaling pathway in the pathogenesis of MAFLD induced by a high-fructose diet mimicking the overconsumption of sugar in humans. This review discusses the possible molecular mechanisms of mTOR-autophagy-endoplasmic reticulum (ER) stress in MAFLD. Based on careful analysis of recent studies, we suggest possible new therapeutic concepts or targets that can be explored for the discovery of new anti-MAFLD drugs.
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Is there an 'ideal' diet for patients with NAFLD?
Pugliese, N, Plaz Torres, MC, Petta, S, Valenti, L, Giannini, EG, Aghemo, A
European journal of clinical investigation. 2022;(3):e13659
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic that encompasses three distinct clinical phenotypes: uncomplicated fatty liver, nonalcoholic steatohepatitis (NASH) and NASH-related cirrhosis with its complications, including hepatocellular carcinoma. To date, no pharmacological treatments have been approved and lifestyle modifications including reduced caloric intake targeting a 7%-10% weight loss from baseline assessment represent the standard approach. Mediterranean diet has been recommended as the best dietary pattern since it is easy to follow and, independently of caloric intake its nutritional components have beneficial metabolic effects that not only improve steatosis but also risk factors for cardiovascular events, the leading cause of morbidity/mortality in individuals with NAFLD. Other dietary patterns such as ketogenic diet and Dietary Approach to Stop Hypertension (DASH) diet can be used in patients with NAFLD. Recently, intermittent fasting diets have gained popularity among healthy individuals and have been proposed as a safe and effective treatment for the metabolic syndrome in experimental and in a few human studies. In this narrative review, we aim to summarize the evidence for the available dietary approaches for patients with NAFLD.
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The role of nutrition in non-alcoholic fatty liver disease treatment in obese children.
Guimber, D, Debray, D, Bocquet, A, Briend, A, Chouraqui, JP, Darmaun, D, Feillet, F, Frelut, ML, Hankard, R, Lapillonne, A, et al
Archives de pediatrie : organe officiel de la Societe francaise de pediatrie. 2022;(1):1-11
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs mostly in the context of insulin resistance and obesity. It has rapidly evolved into the most common cause of liver disease among children. The incidence is high in obese children and a greater risk of disease progression is associated with severe obesity, highlighting the role of nutrition. To date, there is no consensus on NAFLD management. This is a narrative review of clinical studies on the potential benefit of nutritional interventions, including lifestyle modifications, vitamins, docosahexaenoic acid, and probiotics in children with NAFLD. The Comité de nutrition de la Société Française de Pédiatrie (CN-SFP) emphasizes the effect of limiting added sugar intake, i.e., fructose or sucrose-containing beverages, and promoting physical activity in the care of NAFLD.
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Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease.
Valenti, L, Pedica, F, Colombo, M
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2022;(2):154-163
Abstract
Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6-12% vs. 2-3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.
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Adipose tissue insulin resistance and lipidome alterations as the characterizing factors of non-alcoholic steatohepatitis.
Guerra, S, Mocciaro, G, Gastaldelli, A
European journal of clinical investigation. 2022;(3):e13695
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) is now 25% in the general population but increases to more than 55% in subjects with obesity and/or type 2 diabetes. Simple steatosis (NAFL) can develop into more severe forms, that is non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma leading to death. METHODS In this narrative review, we have discussed the current knowledge in the pathophysiology of fatty liver disease, including both metabolic and non-metabolic factors, insulin resistance, mitochondrial function, as well as the markers of liver damage, giving attention to the alterations in lipid metabolism and production of lipotoxic lipids. RESULTS Insulin resistance, particularly in the adipose tissue, is the main driver of NAFLD due to the excess release of fatty acids. Lipidome analyses have shown that several lipids, including DAGs and ceramides, and especially if they contain saturated lipids, act as bioactive compounds, toxic to the cells. Lipids can also affect mitochondrial function. Not only lipids, but also amino acid metabolism is impaired in NAFL/NASH, and some amino acids, as branched-chain and aromatic amino acids, glutamate, serine and glycine, have been linked to impaired metabolism, insulin resistance and severity of NAFLD and serine is a precursor of ceramides. CONCLUSIONS The measurement of lipotoxic species and adipose tissue dysfunction can help to identify individuals at risk of progression to NASH.
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Xiaoyao Powder in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.
Liu, N, Yang, J, Ma, W, Li, C, An, L, Zhang, X, Zou, Q
Journal of ethnopharmacology. 2022;:114999
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide with alarming prevalence. Due to its complex pathogeneses and considerable individual heterogeneity in disease, there is no specific medication to NAFLD safely and effectively. Therefore, there is a great need to explore complementary and alternative therapies. Xiaoyao Powder (XYP), a classic Chinese formula, has been tremendously applied to gastrointestinal diseases, especially non-alcoholic fatty liver disease. However, the efficacy and safety of XYP have not been fully assessed. AIM OF THE STUDY To assess the effectiveness and safety of XYP for NAFLD. MATERIALS AND METHODS The assigned registration number on the PROSPERO platform of this meta-analysis is CRD42020192154, and we strictly followed the protocol. We searched eight primary databases from their inception to June 2020. Two authors independently identified random controlled trials (RCTs) of XYP for NAFLD and evaluated the quality of the retrieved articles by Cochrane accessing risk bias tool. At least one of the following indices was thoroughly documented for outcome measurement: total effective rate, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl transpeptidase (GGT), body mass index (BMI), and adiponectin. We calculated risk ratio (RR) and mean difference (MD) for dichotomous data and continuous variables with a 95% confidence interval (CI). R 4.0.5 software was employed for data synthesis. RESULTS Consequently, we identified 12 studies with 1012 participants. XYP, whether individually or combined with essential treatment, ameliorated NAFLD regardless of the course of the disease or curative duration. This benefit was mainly driven by regulating levels of serum markers, involving TC, TG, ALT, AST, GGT, and adiponectin. Three studies where statins were concerned about drug safety reported several adverse events with clinical symptoms, varying from flatulence, constipation, and diarrhea to rash, whereas others did not. CONCLUSION Our findings provided evidence that XYP is a therapeutic option to treat NAFLD effectively and safely. Notwithstanding, a precise and comprehensive conclusion calls for RCTs on a larger scale with more rigorous designs considering the inferior methodological quality and limited retrieved articles.
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Genome-Wide Association Study of NAFLD Using Electronic Health Records.
Fairfield, CJ, Drake, TM, Pius, R, Bretherick, AD, Campbell, A, Clark, DW, Fallowfield, JA, Hayward, C, Henderson, NC, Joshi, PK, et al
Hepatology communications. 2022;(2):297-308
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Abstract
Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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Subclinical Liver Disease Is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.
Gonzalez-Cantero, A, Teklu, M, Sorokin, AV, Prussick, R, González-Cantero, J, Martin-Rodriguez, JL, Patel, N, Parel, PM, Manyak, GA, Teague, HL, et al
The Journal of investigative dermatology. 2022;(1):88-96
Abstract
Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n = 76 psoriasis participants and 76 controls), nonalcoholic fatty liver disease, assessed by the sonographic hepatorenal index, was more prevalent in psoriasis than in controls (61% vs. 45%; P = 0.04). Participants with psoriasis with nonalcoholic fatty liver disease had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than participants with psoriasis without nonalcoholic fatty liver disease (61% vs. 23%; P = 0.006) and controls with nonalcoholic fatty liver disease (61% vs. 32%; P < 0.05). Sonographic hepatorenal index was a determinant of subclinical atherosclerosis in psoriasis (OR = 3.5; P = 0.01). In the United States cohort (n = 162 participants with psoriasis who underwent positron emission tomography and coronary computed tomography angiography), those with high hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake had higher noncalcified (1.3 [0.49 mm2] vs. 1.0 [0.40 mm2]), fibrofatty (0.23 [0.15 mm2] vs. 0.11 [0.087 mm2]), and lipid-rich necrotic core (4.3 [2.3 mm2] vs. 3.0 [1.7 mm2]) coronary burden (all P < 0.001). Hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake associated with noncalcified (β = 0.28; P < 0.001), fibrofatty (β = 0.49; P < 0.001), and lipid-rich necrotic core (β = 0.28; P = 0.003) burden. These results show the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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Fit mothers for a healthy future: Breaking the intergenerational cycle of non-alcoholic fatty liver disease with maternal exercise.
Stevanović-Silva, J, Beleza, J, Coxito, P, Costa, RC, Ascensão, A, Magalhães, J
European journal of clinical investigation. 2022;(3):e13596
Abstract
UNLABELLED SPECIAL ISSUE 'FOIEGRAS-Bioenergetic Remodelling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease'. BACKGROUND Non-alcoholic fatty liver disease (NAFLD) emerges as significant health burden worldwide. Lifestyle changes, unhealthy dietary habits and physical inactivity, can trigger NAFLD development. Persisting on these habits during pregnancy affects in utero environment and prompts a specific metabolic response in foetus resulting in offspring metabolic maladjustments potentially critical for developing NAFLD later in life. The increasing prevalence of NAFLD, particularly in children, has shifted the research focus towards preventive and therapeutic strategies. Yet, designing effective approaches that can break the NAFLD intergenerational cycle becomes even more complicated. Regular physical exercise (PE) is a powerful non-pharmacological strategy known to counteract deleterious metabolic outcomes. In this narrative review, we aimed to briefly describe NAFLD pathogenesis focusing on maternal nutritional challenge and foetal programming, and to provide potential mechanisms behind the putative intergenerational effect of PE against metabolic diseases, including liver diseases. METHODS Following detailed electronic database search, recent existing evidence about NAFLD development, intergenerational programming and gestational exercise effects was critically analysed and discussed. RESULTS PE during pregnancy could have a great potential to counteract intergenerational transmission of metabolic burden. The interplay between different PE roles-metabolic, endocrine and epigenetic-could offer a more stable in utero environment to the foetus, thus rescuing offspring vulnerability to metabolic disturbances. CONCLUSIONS The better understanding of maternal PE beneficial consequences on offspring metabolism could reinforce the importance of PE during pregnancy as an indispensable strategy in improving offspring health.
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Effects of Insoluble Cereal Fibre on Body Fat Distribution in the Optimal Fibre Trial.
Kabisch, S, Honsek, C, Kemper, M, Gerbracht, C, Meyer, NMT, Arafat, AM, Birkenfeld, AL, Machann, J, Dambeck, U, Osterhoff, MA, et al
Molecular nutrition & food research. 2021;(12):e2000991
Abstract
SCOPE The Optimal Fibre Trial (OptiFiT) investigates metabolic effects of insoluble cereal fibre in subjects with impaired glucose tolerance (IGT), showing moderate glycemic and anti-inflammatory benefits, especially in subjects with an obesity-related phenotype. An OptiFiT sub-group is analysed for effects on body fat distribution. METHODS AND RESULTS 180 participants with IGT receive a blinded, randomized supplementation with insoluble cereal fibre or placebo for 2 years. Once a year, all subjects undergo fasting blood sampling, oral glucose tolerance test, and anthropometric measurements. A subgroup (n=47) also received magnetic resonance imaging and spectroscopy for quantification of adipose tissue distribution and liver fat content. We compared MR, metabolic and inflammatory outcomes between fibre and placebo group metabolism and inflammation. Visceral and non-visceral fat, fasting glucose, HbA1c, fasting insulin, insulin resistance, and uric acid decrease only in the fibre group, mirroring effects of the entire cohort. However, after adjustment for weight loss, there are no significant between-group differences. There is a statistical trend for fibre-driven liver fat reduction in subjects with confirmed non-alcoholic fatty liver disease (NAFLD; n = 19). CONCLUSIONS Data and evidence on beneficial effects of insoluble cereal fibre on visceral and hepatic fatstorage is limited, but warrants further research. Targeted trials are required.