-
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
-
-
Free full text
-
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.
-
2.
Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology.
Della Torre, S
Cells. 2021;(9)
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, being frequently associated with obesity, unbalanced dietary regimens, and reduced physical activity. Despite their greater adiposity and reduced physical activity, women show a lower risk of developing NAFLD in comparison to men, likely a consequence of a sex-specific regulation of liver metabolism. In the liver, sex differences in the uptake, synthesis, oxidation, deposition, and mobilization of lipids, as well as in the regulation of inflammation, are associated with differences in NAFLD prevalence and progression between men and women. Given the major role of sex hormones in driving hepatic sexual dimorphism, this review will focus on the role of sex hormones and their signaling in the regulation of hepatic metabolism and in the molecular mechanisms triggering NAFLD development and progression.
-
3.
Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches.
Dongiovanni, P, Paolini, E, Corsini, A, Sirtori, CR, Ruscica, M
European journal of clinical investigation. 2021;(7):e13519
-
-
Free full text
-
Abstract
BACKGROUND A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated fatty liver disease (MAFLD), to describe more appropriately the liver disease related to metabolic derangements. MAFLD is closely intertwined with type 2 diabetes, obesity, dyslipidaemia, all linked to a rise in the risk of cardiovascular disease (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises the odds of CVD, the present review aims to evaluate the impact of NAFLD/MAFLD aetiologies on CV health and the potential correction by dietary and drug approaches. RESULTS Epidemiological studies indicate that NAFLD raises risk of fatal or non-fatal CVD events. NAFLD patients have a higher prevalence of arterial plaques and stiffness, coronary calcification, and endothelial dysfunction. Although genetic and environmental factors strongly contribute to NAFLD pathogenesis, a Mendelian randomization analysis indicated that the PNPLA3 genetic variant leading to NAFLD may not be causally associated with CVD risk. Among other genetic variants related to NAFLD, TM6SF2 appears to be protective, whereas MBOAT7 may favour venous thromboembolism. CONCLUSIONS NAFLD is correlated to a higher CVD risk which may be ameliorated by dietary interventions. This is not surprising, since new criteria defining MAFLD include other metabolic risk abnormalities fuelling development of serious adverse extrahepatic outcomes, for example CVD. The present lack of a targeted pharmacological approach makes the identification of patients with liver disease at higher CVD risk (eg diabetes, hypertension, obesity or high levels of C-reactive protein) of major clinical interest.
-
4.
Understanding the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease and Its Role in Hepatocellular Carcinoma: A Review of Novel Insights.
Mass Sanchez, PB, Krizanac, M, Weiskirchen, R, Asimakopoulos, A
International journal of molecular sciences. 2021;(10)
Abstract
Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and translational activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression of NAFLD to HCC.
-
5.
The role of the gut microbiome and its metabolites in metabolic diseases.
Wu, J, Wang, K, Wang, X, Pang, Y, Jiang, C
Protein & cell. 2021;(5):360-373
Abstract
It is well known that an unhealthy lifestyle is a major risk factor for metabolic diseases, while in recent years, accumulating evidence has demonstrated that the gut microbiome and its metabolites also play a crucial role in the onset and development of many metabolic diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular disease and so on. Numerous microorganisms dwell in the gastrointestinal tract, which is a key interface for energy acquisition and can metabolize dietary nutrients into many bioactive substances, thus acting as a link between the gut microbiome and its host. The gut microbiome is shaped by host genetics, immune responses and dietary factors. The metabolic and immune potential of the gut microbiome determines its significance in host health and diseases. Therefore, targeting the gut microbiome and relevant metabolic pathways would be effective therapeutic treatments for many metabolic diseases in the near future. This review will summarize information about the role of the gut microbiome in organism metabolism and the relationship between gut microbiome-derived metabolites and the pathogenesis of many metabolic diseases. Furthermore, recent advances in improving metabolic diseases by regulating the gut microbiome will be discussed.
-
6.
Non-Alcoholic Fatty Liver Disease in Obese Youth With Insulin Resistance and Type 2 Diabetes.
Scapaticci, S, D'Adamo, E, Mohn, A, Chiarelli, F, Giannini, C
Frontiers in endocrinology. 2021;:639548
Abstract
Currently, Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent form of chronic liver disease in children and adolescents worldwide. Simultaneously to the epidemic spreading of childhood obesity, the rate of affected young has dramatically increased in the last decades with an estimated prevalence of NAFLD of 3%-10% in pediatric subjects in the world. The continuous improvement in NAFLD knowledge has significantly defined several risk factors associated to the natural history of this complex liver alteration. Among them, Insulin Resistance (IR) is certainly one of the main features. As well, not surprisingly, abnormal glucose tolerance (prediabetes and diabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. In addition, other factors such as genetic, ethnicity, gender, age, puberty and lifestyle might affect the development and progression of hepatic alterations. However, available data are still lacking to confirm whether IR is a risk factor or a consequence of hepatic steatosis. There is also evidence that NAFLD is the hepatic manifestation of Metabolic Syndrome (MetS). In fact, NAFLD often coexist with central obesity, impaired glucose tolerance, dyslipidemia, and hypertension, which represent the main features of MetS. In this Review, main aspects of the natural history and risk factors of the disease are summarized in children and adolescents. In addition, the most relevant scientific evidence about the association between NAFLD and metabolic dysregulation, focusing on clinical, pathogenetic, and histological implication will be provided with some focuses on the main treatment options.
-
7.
Metabolic-Associated Fatty Liver Disease (MAFLD), Diabetes, and Cardiovascular Disease: Associations with Fructose Metabolism and Gut Microbiota.
Drożdż, K, Nabrdalik, K, Hajzler, W, Kwiendacz, H, Gumprecht, J, Lip, GYH
Nutrients. 2021;(1)
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition associated with type 2 diabetes (T2DM) and cardiovascular disease (CVD). Since systemic metabolic dysfunction underlies NAFLD, the current nomenclature has been revised, and the term metabolic-associated fatty liver disease (MAFLD) has been proposed. The new definition emphasizes the bidirectional relationships and increases awareness in looking for fatty liver disease among patients with T2DM and CVD or its risk factors, as well as looking for these diseases among patients with NAFLD. The most recommended treatment method of NAFLD is lifestyle changes, including dietary fructose limitation, although other treatment methods of NAFLD have recently emerged and are being studied. Given the focus on the liver-gut axis targeting, bacteria may also be a future aim of NAFLD treatment given the microbiome signatures discriminating healthy individuals from those with NAFLD. In this review article, we will provide an overview of the associations of fructose consumption, gut microbiota, diabetes, and CVD in patients with NAFLD.
-
8.
Nutritional Approaches for the Management of Nonalcoholic Fatty Liver Disease: An Evidence-Based Review.
Parra-Vargas, M, Rodriguez-Echevarria, R, Jimenez-Chillaron, JC
Nutrients. 2020;(12)
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide representing a public health issue. Its coexistence with obesity and other metabolic alterations is highly frequent. Therefore, current therapy interventions for NAFLD are mainly focused on progressive weight loss through modulation of overall calorie intake with or without specific macronutrient adjustments. Furthermore, other relevant nutritional interventions are built on food selection and time-restricted eating. Since every strategy might bring different results, choosing the optimal diet therapy for a patient is a complicated task, because NAFLD is a multifactorial complex disease. Importantly, some factors need to be considered, such as nutrition-based evidence in terms of hepatic morphophysiological improvements as well as adherence of the patient to the meal plan and adaptability in their cultural context. Thus, the purpose of this review is to explore and compare the subtleties and nuances of the most relevant clinical practice guidelines and the nutritional approaches for the management of NAFLD with a special attention to tangible outcomes and long-term adherence.
-
9.
Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease.
Li, R, Toan, S, Zhou, H
Aging. 2020;(7):6467-6485
Abstract
Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.
-
10.
Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants.
Rives, C, Fougerat, A, Ellero-Simatos, S, Loiseau, N, Guillou, H, Gamet-Payrastre, L, Wahli, W
Biomolecules. 2020;(12)
Abstract
Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.