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Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown antifibrogenic and anti-inflammatory effects in vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells. [ABSTRACT FROM AUTHOR]

The frequency of non-alcoholic fatty liver disease (NAFLD) has intensified, creating diagnostic challenges and increasing the need for reliable non-invasive diagnostic tools. Due to the importance of the gut–liver axis in the progression of NAFLD, studies attempt to reveal microbial signatures in NAFLD, evaluate them as diagnostic biomarkers, and to predict disease progression. The gut microbiome affects human physiology by processing the ingested food into bioactive metabolites. These molecules can penetrate the portal vein and the liver to promote or prevent hepatic fat accumulation. Here, the findings of human fecal metagenomic and metabolomic studies relating to NAFLD are reviewed. The studies present mostly distinct, and even contradictory, findings regarding microbial metabolites and functional genes in NAFLD. The most abundantly reproducing microbial biomarkers include increased lipopolysaccharides and peptidoglycan biosynthesis, enhanced degradation of lysine, increased levels of branched chain amino acids, as well as altered lipid and carbohydrate metabolism. Among other causes, the discrepancies between the studies may be related to the obesity status of the patients and the severity of NAFLD. In none of the studies, except for one, was diet considered, although it is an important factor driving gut microbiota metabolism. Future studies should consider diet in these analyses. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that affects approximately one-quarter of the global adult population, posing a significant threat to human health with wide-ranging social and economic implications. The main characteristic of NAFLD is considered that the excessive fat is accumulated and deposited in hepatocytes without excess alcohol intake or some other pathological causes. NAFLD is a progressive disease, ranging from steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Therefore, NAFLD will probably emerge as the leading cause of end-stage liver disease in the coming decades. Unlike other highly prevalent diseases, NAFLD has received little attention from the global public health community. Liver biopsy is currently considered the gold standard for the diagnosis and staging of NAFLD because of the absence of noninvasive and specific biomarkers. Due to the complex pathophysiological mechanisms of NAFLD and the heterogeneity of the disease phenotype, no specific pharmacological therapies have been approved for NAFLD at present, although several drugs are in advanced stages of development. This review summarizes the current evidence on the pathogenesis, diagnosis and treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed. [ABSTRACT FROM AUTHOR]

To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios. [ABSTRACT FROM AUTHOR]

Bile acids synthesized within the hepatocytes are transformed by gut microorganisms and reabsorbed into the portal circulation. During their enterohepatic cycling, bile acids act as signaling molecules by interacting with receptors to regulate pathways involved in many physiological processes. The bile acid pool, composed of a variety of bile acid species, has been shown to be altered in diseases, hence contributing to disease pathogenesis. Thus, understanding the changes in bile acid pool size and composition in pathological processes will help to elaborate effective pharmacological treatments. Five crucial steps along the enterohepatic cycle shape the bile acid pool size and composition, offering five possible targets for therapeutic intervention. In this review, we provide an insight on the strategies to modulate the bile acid pool, and then we discuss the potential benefits in non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. A range of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the pathogenesis of NAFLD and some natural products that have been shown to have therapeutic effects on NAFLD. Our work shows that natural products can be a potential therapeutic option for NAFLD. [ABSTRACT FROM AUTHOR]

Cholesterol synthesis occurs in almost all cells, but mainly in hepatocytes in the liver. Cholesterol is garnering increasing attention for its central role in various metabolic diseases. In addition, cholesterol is one of the most essential elements for cells as both a structural source and a player participating in various metabolic pathways. Accurate regulation of cholesterol is necessary for the proper metabolism of fats in the body. Disturbances in cholesterol homeostasis have been linked to various metabolic diseases, such as hyperlipidemia and non-alcoholic fatty liver disease (NAFLD). For many years, the use of synthetic chemical drugs has been effective against many health conditions. Furthermore, from ancient to modern times, various plant-based drugs have been considered local medicines, playing important roles in human health. Phytochemicals are bioactive natural compounds that are derived from medicinal plants, fruit, vegetables, roots, leaves, and flowers and are used to treat a variety of diseases. They include flavonoids, carotenoids, polyphenols, polysaccharides, vitamins, and more. Many of these compounds have been proven to have antioxidant, anti-inflammatory, antiobesity and antihypercholesteremic activity. The multifaceted role of phytochemicals may provide health benefits to humans with regard to the treatment and control of cholesterol metabolism and the diseases associated with this disorder, such as NAFLD. In recent years, global environmental climate change, the COVID-19 pandemic, the current war in Europe, and other conflicts have threatened food security and human nutrition worldwide. This further emphasizes the urgent need for sustainable sources of functional phytochemicals to be included in the food industry and dietary habits. This review summarizes the latest findings on selected phytochemicals from sustainable sources—algae and edible mushrooms—that affect the synthesis and metabolism of cholesterol and improve or prevent NAFLD. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. Acute kidney injury (AKI) is a class of clinical conditions characterized by a rapid decline in kidney function. NAFLD and AKI, as major public health diseases with high prevalence and mortality, respectively, worldwide, place a heavy burden on societal healthcare systems. Clinical observations of patients with NAFLD with AKI suggest a possible association between the two diseases. However, little is known about the pathogenic mechanisms linking NAFLD and AKI, and the combination of the diseases is poorly treated. Previous studies have revealed that liver-derived factors are transported to distal organs via circulation, such as the kidney, where they elicit specific effects. Of note, while NAFLD affects the expression of many hepatic factors, studies on the mechanisms whereby NAFLD mediates the generation of hepatic factors that lead to AKI are lacking. Considering the unique positioning of hepatic factors in coordinating systemic energy metabolism and maintaining energy homeostasis, we hypothesize that the effects of NAFLD are not only limited to the structural and functional changes in the liver but may also involve the entire body via the hepatic factors, e.g., playing an important role in the development of AKI. This raises the question of whether analogs of beneficial hepatic factors or inhibitors of detrimental hepatic factors could be used as a treatment for NAFLD-mediated and hepatic factor-driven AKI or other metabolic disorders. Accordingly, in this review, we describe the systemic effects of several types of hepatic factors, with a particular focus on the possible link between hepatic factors whose expression is altered under NAFLD and AKI. We also summarize the role of some key hepatic factors in metabolic control mechanisms and discuss their possible use as a preventive treatment for the progression of metabolic diseases. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease is a huge cause of chronic liver failure around the world. This condition has become more prevalent as rates of metabolic syndrome, type 2 diabetes, and obesity have also escalated. The unfortunate outcome for many people is liver cirrhosis that warrants transplantation or being unable to receive a transplant since many livers are discarded due to high levels of steatosis. Over the past several years, however, a great deal of work has gone into understanding the pathophysiology of this disease as well as possible treatment options. This review summarizes various defatting strategies including in vitro use of pharmacologic agents, machine perfusion of extracted livers, and genomic approaches targeting specific proteins. The goal of the field is to reduce the number of necessary transplants and expand the pool of organs available for use. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on its mechanism and therapeutic strategy. With the development of the gut–liver axis theory, the association between the gut–liver axis and the pathogenesis of NAFLD has been gradually disclosed. Polysaccharides, as a kind of natural product, have the advantages of low toxicity, multi-target and multi-pathway action. It has been reported that polysaccharides can affect the gut–liver axis at multiple interrelated levels, such as maintaining the ecological balance of gut microbiota (GM), regulating the metabolites of GM and improving the intestinal barrier function, which thereby plays a protective role in NAFLD. These studies have great scientific significance in understanding NAFLD based on the gut–liver axis and developing safe and effective medical treatments. Herein, we reviewed the recent progress of polysaccharides in improving nonalcoholic fatty liver disease (NAFLD) through the gut–liver axis. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) represents an increasing cause of liver disease, affecting one-third of the population worldwide. Despite many medications being in the pipeline to treat the condition, there is still no pharmaceutical agent licensed to treat the disease. As intestinal bacteria play a crucial role in the pathogenesis and progression of liver damage in patients with NAFLD, it has been suggested that manipulating the microbiome may represent a therapeutical option. In this review, we summarise the latest evidence supporting the manipulation of the intestinal microbiome as a potential therapy for treating liver disease in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver disease, is strongly correlated with obesity, insulin resistance, metabolic syndrome, and genetic components. The pathological progression of NAFLD, consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and liver cirrhosis, is characterized by a broad spectrum of clinical phenotypes. Although patients with mild NAFL are considered to show no obvious clinical symptoms, patients with long-term NAFL may culminate in NASH and further liver fibrosis. Even though various drugs are able to improve NAFLD, there are no FDA-approved medications that directly treat NAFLD. In this paper, the pathogenesis of NAFLD, the potential therapeutic targets, and their underlying mechanisms of action were reviewed. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Retinol-binding protein 4 (RBP4) has been considered to be related to metabolic related diseases, such as hyperuricemia, obesity, and diabetes mellitus. However, whether nonalcoholic fatty liver disease (NAFLD) is related to RBP4 is unclear. Previous studies on the relationship between NAFLD and RBP4 levels have yielded inconsistent results. Hence, this meta-analysis was aimed to clarify whether circulating RBP4 levels are in relation to the risk of NAFLD. Methods: A meta-analysis was performed by applying observational studies to evaluate circulating RBP4 levels and NAFLD. Eligible studies published up to September 23, 2022, were searched in Embase, PubMed, and Cochrane databases. Results: In this study, 17 cross-sectional studies involving 8423 participants were included. Results from a random effects model showed that circulating RBP4 levels were higher in NAFLD patients than non-NAFLD (standardized mean difference (SMD) 0.28; 95% confidence intervals (CI): 0.11–0.46, I2: 89.8%). This association was confirmed in the Yellow race. However, no significant association was noted in the Caucasian race. After excluding the morbidly obese Population from the weight loss study (n = 2), the results of the comparison remained largely unchanged (SMD 0.28; 95% CI: 0.10–0.47, I2: 90.8%). Remarkable publication bias was not found. Although considerable heterogeneity was observed among the studies, no potential sources of heterogeneity were found in the subgroup analysis. Diagnostic methods for NAFLD were determined to be a potential source of statistical heterogeneity in meta-regression. Conclusion: The findings provide evidence that NAFLD patients exhibit higher levels of circulating RBP4 compared with controls, but high heterogeneity was observed. Thus, a high RBP4 level is probably a potential risk factor for NAFLD. To confirm the causal link between NAFLD and RBP4 level of causality, further prospective cohort studies are needed. [ABSTRACT FROM AUTHOR]

Background: About 25% of the global population suffers from non-alcoholic fatty liver disease (NAFLD), making it the most prevalent form of liver disease. One form of NAFLD, nonalcoholic steatohepatitis (NASH), can ultimately lead to cirrhosis, hepatocellular carcinoma (HCC), and mortality. The most common causes of fatty liver disease are being overweight or obese, having insulin resistance, leading an inactive lifestyle, consuming a high-fat diet and having a family history of the condition. The pathogenesis of NAFLD is associated with a weaker intestinal barrier caused by an altered gut microbiota, which exposes the host to bacterial components and triggers immunological defense and inflammation pathways via toll-like receptor signalling, ultimately leading to the development of NASH. The objective of the present review article is to discuss the risk factors and pathophysiological pathways that lead to NAFLD. Development: PubMed, Google scholar and Science direct were searched using the following keywords: Steatohepatitis, Steatosis, Hepatocellular carcinoma, Metabolic syndrome, Dysbiosis and Non-alcoholic fatty liver disease. The authors also screened references from the relevant literature, including all the identified studies and reviews, only the most recent or complete study was included between December 2002 and April 2021. Documents in a language apart from English have been excluded as sources for interpretation was not found. Papers apart from main scientific studies had been excluded: documents unavailable as total written text, conversation, conference abstract papers and dissertations. Conclusion: Globally, NAFLD is the most prevalent form of chronic liver disease. The pathophysiology of NAFLD is complex and requires the interaction of multiple factors. Metabolic syndrome, insulin resistance, unhealthy dietary habits and gut microbiota play major roles for the development of NAFLD. [ABSTRACT FROM AUTHOR]

Modifications in the microbiota caused by environmental and genetic reasons can unbalance the intestinal homeostasis, deregulating the host's metabolism and immune system, intensifying the risk factors for the development and aggravation of non-alcoholic fat liver disease (NAFLD). The use of probiotics, prebiotics and synbiotics have been considered a potential and promising strategy to regulate the gut microbiota and produce beneficial effects in patients with liver conditions. For this reason, this review aimed to evaluate the effectiveness of probiotics, prebiotics, and symbiotics in patients with NAFLD and NASH. Pubmed, Embase, and Cochrane databases were consulted, and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines were followed. The clinical trials used in this study demonstrated that gut microbiota interventions could improve a wide range of markers of inflammation, glycemia, insulin resistance, dyslipidemia, obesity, liver injury (decrease of hepatic enzymes and steatosis and fibrosis). Although microbiota modulators do not play a healing role, they can work as an important adjunct therapy in pathological processes involving NAFLD and its spectrums, either by improving the intestinal barrier or by preventing the formation of toxic metabolites for the liver or by acting on the immune system. [ABSTRACT FROM AUTHOR]

Metabolic diseases have become a serious threat to human health worldwide. It is crucial to look for effective drugs from natural products to treat metabolic diseases. Curcumin, a natural polyphenolic compound, is mainly obtained from the rhizomes of the genus Curcuma. In recent years, clinical trials using curcumin for the treatment of metabolic diseases have been increasing. In this review, we provide a timely and comprehensive summary of the clinical progress of curcumin in the treatment of three metabolic diseases, namely type 2 diabetes mellitus (T2DM), obesity and non-alcoholic fatty liver disease (NAFLD). The therapeutic effects and underlying mechanisms of curcumin on these three diseases are presented categorically. Accumulating clinical evidence demonstrates that curcumin has good therapeutic potential and a low number of side effects for the three metabolic diseases. It can lower blood glucose and lipid levels, improve insulin resistance and reduce inflammation and oxidative stress. Overall, curcumin may be an effective drug for the treatment of T2DM, obesity and NAFLD. However, more high-quality clinical trials are still required in the future to verify its efficacy and determine its molecular mechanisms and targets. [ABSTRACT FROM AUTHOR]

The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is considered the most frequent chronic hepatic disease in the general population, while it is the first cause of liver transplantation in the US. NAFLD patients will subsequently develop non-alcoholic steatohepatitis (NASH), which is characterized by aberrant hepatocellular inflammation with or without the presence of fibrosis. The lack of specific biomarkers and therapeutic strategies makes non-alcoholic steatohepatitis (NASH) management a difficult task for clinicians. Extracellular vesicles (EVs) constitute a heterogenic population of vesicles produced by inward or outward plasma-membrane budding. There is an emerging connection between autophagy EVs production, via an unconventional non-degradative procedure. Alterations in the amount of the secreted EVs and the cargo they carry are also involved in the disease progression and development of NASH. Autophagy constitutes a multistep lysosomal degradative pathway that reassures cell homeostasis and survival under stressful conditions, such as oxygen and energy deprivation. It prevents cellular damage by eliminating defected proteins or nοn-functional intracellular organelles. At the same time, it reassures the optimal conditions for the cells via a different mechanism that includes the removal of cargo via the secretion of EVs. Similarly, autophagy machinery is also associated with the pathogenetic mechanism of NAFLD, while it has a significant implication for the progression of the disease and the development of NASH. In this review, we will shed light on the interplay between autophagy and EVs in NASH, the emerging connection of EVs production with the autophagy pathway, and their possible manipulation for developing future therapeutic strategies for NASH. [ABSTRACT FROM AUTHOR]

Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance. [ABSTRACT FROM AUTHOR]

Accumulating evidence now indicates that non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease observed in clinical practice worldwide, is independently associated with an increased risk of incident chronic kidney disease (CKD). Given that NAFLD is linked to insulin resistance, obesity and type 2 diabetes mellitus, an international panel of experts have recently proposed a name change from NAFLD to metabolic associated fatty liver disease (MAFLD). Since the diagnostic criteria for NAFLD and MAFLD are different, observational studies assessing the potential concordance (or even superiority) of MAFLD, compared with NAFLD, in detecting patients at increased risk of hepatic and extra-hepatic complications (including CKD) are required. Hence, in the last two years, some observational studies have investigated the potential relationship between MAFLD and CKD. The result is that, at present, evidence regarding the concordance or even superiority of MAFLD, compared with NAFLD, in detecting patients at higher risk of CKD is still preliminary, although some data indicate that MAFLD identifies patients with CKD as accurately as NAFLD. In this narrative review, we will discuss: (a) the epidemiological evidence assessing the association between NAFLD and risk of incident CKD, (b) the epidemiological data investigating the association between MAFLD and risk of CKD and (c) the biological mechanisms underlying the association between NAFLD/MAFLD and CKD. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) has emerged as the third "gasotransmitters" and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced. [ABSTRACT FROM AUTHOR]

Acute and chronic hepatic damages are caused by xenobiotics or different diseases affecting the liver, characterized by different etiologies and pathological features. It has been demonstrated extensively that liver damage progresses differently in men and women, and some chronic liver diseases show a more favorable prognosis in women than in men. This review aims to update the most recent advances in the comprehension of the molecular basis of the sex difference observed in both acute and chronic liver damage. With this purpose, we report experimental studies on animal models and clinical observations investigating both acute liver failure, e.g., drug-induced liver injury (DILI), and chronic liver diseases, e.g., viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), autoimmune liver diseases, and hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

Background: Lipid accumulation product (LAP) is an index calculated by waist circumference (WC) and triglyceride (TG), which reflects lipid toxicity. This study aims to investigate the association between the LAP index and nonalcoholic fatty liver disease (NAFLD) in a systematic review and meta-analysis. Methods and results: PubMed, Scopus, and Web of Science online databases were searched for eligible studies that investigated the association of the LAP index and NAFLD. Sixteen observational studies with 96,101 participants, including four cohort studies, one case‒control study and 11 cross-sectional studies with baseline data, were entered into this analysis. Fourteen studies reported a significant association between the LAP index and NAFLD, and two reported that this relation was not significant; two different meta-analyses (1- mean difference (MD) and 2- bivariate diagnostic test accuracy [DTA]) were conducted using Stata version 14. The LAP index was compared in subjects with and without NAFLD, and the difference was significant with 34.90 units (CI 95: 30.59–39.31, P < 0.001) of the LAP index. The DTA meta-analysis was conducted and showed that the LAP index pooled sensitivity and specificity for screening of NAFLD were 94% (CI95: 72%–99%, I2 = 99%, P < 0.001) and 85% (CI95: 62%–96%, I2 = 99%, P < 0.001), respectively. Conclusion: The LAP Index is an inexpensive, sensitive, and specific method to evaluate NAFLD and may be valuable for NAFLD screening. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD. [ABSTRACT FROM AUTHOR]

The microbial-derived products, including short chain fatty acids, lipopolysaccharide and secondary bile acids, have been shown to participate in the regulation of hepatic lipid metabolism. Previous studies have demonstrated that prebiotics, such as oligosaccharide and inulin, have abilities to change the concentration of microbial-derived products through modulating the microbial community structure, thus controlling body weight and alleviating hepatic fat accumulation. However, recent evidence indicates that there are individual differences in host response upon inulin treatment due to the differences in host microbial composition before dietary intervention. Probably it is because of the multiple relationships among bacterial species (e.g., competition and mutualism), which play key roles in the degradation of inulin and the regulation of microbial structure. Thereby, analyzing the composition and function of initial gut microbiota is essential for improving the efficacy of prebiotics supplementation. Furthermore, considering that different structures of polysaccharides can be used by different microorganisms, the chemical structure of processed inulin should be tested before using prebiotic inulin to treat obesity related nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

O-linked b-N-acetyl-glucosaminylation (O-GlcNAcylation) is one of the most common post-translational modifications of proteins, and is established by modifying the serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc signaling is considered a critical nutrient sensor, and affects numerous proteins involved in cellular metabolic processes. O-GlcNAcylation modulates protein functions in different patterns, including protein stabilization, enzymatic activity, transcriptional activity, and protein interactions. Disrupted O-GlcNAcylation is associated with an abnormal metabolic state, and may result in metabolic disorders. As the liver is the center of nutrient metabolism, this review provides a brief description of the features of the O-GlcNAc signaling pathway, and summarizes the regulatory functions and underlying molecular mechanisms of O-GlcNAcylation in liver metabolism. Finally, this review highlights the role of O-GlcNAcylation in liver-associated diseases, such as diabetes and nonalcoholic fatty liver disease (NAFLD). We hope this review not only benefits the understanding of O-GlcNAc biology, but also provides new insights for treatments against liver-associated metabolic disorders. [ABSTRACT FROM AUTHOR]

Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis. [ABSTRACT FROM AUTHOR]

It is a generally accepted model that environmental influences can exert their effects, at least in part, by changing the molecular regulators of transcription that are described as epigenetic. As there is biochemical evidence that some epigenetic regulators of transcription can maintain their states long term and through cell division, an epigenetic model encompasses the idea of maintenance of the effect of an exposure long after it is no longer present. The evidence supporting this model is mostly from the observation of alterations of molecular regulators of transcription following exposures. With the understanding that the interpretation of these associations is more complex than originally recognised, this model may be oversimplistic; therefore, adopting novel perspectives and experimental approaches when examining how environmental exposures are linked to phenotypes may prove worthwhile. In this review, we have chosen to use the example of nonalcoholic fatty liver disease (NAFLD), a common, complex human disease with strong environmental and genetic influences. We describe how epigenomic approaches combined with emerging functional genetic and single-cell genomic techniques are poised to generate new insights into the pathogenesis of environmentally influenced human disease phenotypes exemplified by NAFLD. [ABSTRACT FROM AUTHOR]

NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups—hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management. [ABSTRACT FROM AUTHOR]

As a member of the miR-1 family, miR-206 is located between IL-17 and PKHD1 genes in human. This miRNA has been shown to be involved in the pathogenic processes in a variety of human disorders including cancers, amyotrophic lateral sclerosis, Alzheimer's disease, atherosclerosis, bronchopulmonary dysplasia, coronary artery disease, chronic obstructive pulmonary disease, epilepsy, nonalcoholic fatty liver disease, Hirschsprung disease, muscular dystrophies, pulmonary arterial hypertension, sepsis and ulcerative colitis. In the current review, we summarize the role of miR-206 in both malignant and non-malignant situations and explain its possible therapeutic implications. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR), designated as the blunted response of insulin target tissues to physiological level of insulin, plays crucial roles in the development and progression of diabetes, nonalcoholic fatty liver disease (NAFLD) and other diseases. So far, the distinct mechanism(s) of IR still needs further exploration. Long non-coding RNA (lncRNA) is a class of non-protein coding RNA molecules with a length greater than 200 nucleotides. LncRNAs are widely involved in many biological processes including cell differentiation, proliferation, apoptosis and metabolism. More recently, there has been increasing evidence that lncRNAs participated in the pathogenesis of IR, and the dysregulated lncRNA profile played important roles in the pathogenesis of metabolic diseases including obesity, diabetes and NAFLD. For example, the lncRNAs MEG3, H19, MALAT1, GAS5, lncSHGL and several other lncRNAs have been shown to regulate insulin signaling and glucose/lipid metabolism in various tissues. In this review, we briefly introduced the general features of lncRNA and the methods for lncRNA research, and then summarized and discussed the recent advances on the roles and mechanisms of lncRNAs in IR, particularly focused on liver, skeletal muscle and adipose tissues. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD)/metabolic associated fatty liver disease (MAFLD) is becoming a public health problem worldwide. Steatosis as the simple form and nonalcoholic steatohepatitis (NASH) as its progression form are commonly seen in liver biopsy specimens from patients with obesity, diabetes, hyperlipidemia, hypertension, and the use of certain drugs. Patients with NASH and advanced fibrosis were associated with increased risks of liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanisms regarding the progression from simple steatosis to NASH fibrosis remain incompletely understood. Because NASH-caused liver injury is a complex process and multiple cell types are involved, intercellular communication is likely mediated by extracellular vesicles. Exosomes are a type of small extracellular vesicles and contain various cellular molecules, including proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs). MiRNAs are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and may play an important role in the pathogenesis of NALFD/NASH. In this article, we review the articles about NASH and exosomal miRNAs published in the most recent English literature through PubMed search and discuss the most recent criteria for histological diagnosis, pathogenesis from steatosis to NASH, roles of exosomal miRNAs in NASH pathogenesis and progression, as well as their potential in future clinical diagnosis and treatment for patients with NASH. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD. [ABSTRACT FROM AUTHOR]

The present review aims at analyzing the current evidence regarding probiotic administration for non-alcoholic fatty liver disease (NAFLD) management. Additionally, the involved mechanisms of action modulated by probiotic administration, as well as the eventual limitations of this therapeutic approach and potential alternatives, are discussed. Preclinical studies have demonstrated that the administration of single-strain probiotics and probiotic mixtures effectively prevents diet-induced NAFLD. In both cases, the magnitude of the described effects, as well as the involved mechanisms of action, are comparable, including reduced liver lipid accumulation (due to lipogenesis downregulation and fatty acid oxidation upregulation), recovery of gut microbiota composition and enhanced intestinal integrity. Similar results have also been reported in clinical trials, where the administration of probiotics proved to be effective in the treatment of NAFLD in patients featuring this liver condition. In this case, information regarding the mechanisms of action underlying probiotics-mediated hepatoprotective effects is scarcer (mainly due to the difficulty of liver sample collection). Since probiotics administration represents an increased risk of infection in vulnerable subjects, much attention has been paid to parabiotics and postbiotics, which seem to be effective in the management of several metabolic diseases, and thus represent a suitable alternative to probiotic usage. [ABSTRACT FROM AUTHOR]

Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches. Donath and colleagues review how chronic tissue inflammation results in insulin resistance, impaired insulin secretion, glucose intolerance, and type 2 diabetes. They discuss the impact of inflammation on diabetic complications, current therapeutic options for the treatment of metabolic disease, and the potential of immune-modulatory approaches. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Studies have demonstrated the link between vitamin-D-related genetic variations and nonskeletal outcomes. We aimed to identify all available data on the association of vitamin-D-related genetic variations with nonalcoholic fatty liver disease (NAFLD). Methods: Potentially eligible studies were identified from Embase and Medline databases from inception to June 2022 using a search strategy that comprised terms for "Vitamin D" and "NAFLD". Eligible studies must report the association between vitamin D-related genetic variations and presence, severity or response to treatment of NAFLD. Data were extracted from each eligible study. Results: A total of 3495 articles were identified. After a systematic review, twelve studies were included. A total of 26 genetic variations were identified. Presence of NAFLD was associated with variations of GC (rs222054, rs222020, rs10011000, rs7041), VDR (rs2228570, rs11168287, rs10783219, rs4752), CYP24A1 (rs3787557, rs6068816, rs2296241, rs2248359) and CYP27B1 (rs4646536). Severity of NAFLD was associated with variations of GC (rs4588), VDR (rs2228570, rs4334089), CYP2R1 (rs10741657), DHCR7 (rs1544410, rs3829251, rs12785878) and CYP24A1 (rs3787557, rs6068816, rs6097809, rs6127119, rs2248359, rs3787554, rs4809960, rs6022999). Response to calcitriol treatment was associated with variation of VDR (rs10735810). Conclusions: Multiple vitamin D-related genetic variations were associated with NAFLD, indicating the role of vitamin D in the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is found in up to 30% of the world's population and can lead to hepatocellular carcinoma (HCC), which has a poor 5-year relative survival rate of less than 40%. Clinical therapeutic strategies are not very successful. The co-occurrence of metabolic disorders and inflammatory environments during the development of steatohepatitis thus needs to be more specifically diagnosed and treated to prevent fatal HCC development. To improve diagnostic and therapeutic strategies, the identification of molecules and/or pathways responsible for the initiation and progression of chronic liver disease has been explored in many studies, but further study is still required. Transmembrane 4 L six family member 5 (TM4SF5) has been observed to play roles in the regulation of metabolic functions and activities in hepatocytes using in vitro cell and in vivo animal models without or with TM4SF5 expression in addition to clinical liver tissue samples. TM4SF5 is present on the membranes of different organelles or vesicles and cooperates with transporters for fatty acids, amino acids, and monocarbohydrates, thus regulating nutrient uptake into hepatocytes and metabolism and leading to phenotypes of chronic liver diseases. In addition, TM4SF5 can remodel the immune environment by interacting with immune cells during TM4SF5-mediated chronic liver diseases. Because TM4SF5 may act as an NAFLD biomarker, this review summarizes crosstalk between TM4SF5 and nutrient transporters in hepatocytes, which is related to chronic liver diseases. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted the world and caused the 2019 coronavirus disease (COVID-19) pandemic. The clinical manifestations of the virus can vary from patient to patient, depending on their respective immune system and comorbidities. SARS-CoV-2 can affect patients through two mechanisms: directly by targeting specific receptors or by systemic mechanisms. We reviewed data in the latest literature in order to discuss and determine the risk of new-onset liver injuries due to COVID-19 in preexisting hepatic conditions. The particular expression of angiotensin-converting enzyme 2 (ACE2) receptors is an additional risk factor for patients with liver disease. COVID-19 causes more severe forms in patients with non-alcoholic fatty liver disease (NAFLD), increases the risk of cirrhosis decompensation, and doubles the mortality for these patients. The coinfection SARS-CoV-2—viral hepatitis B or C might have different outcomes depending on the stage of the liver disease. Furthermore, the immunosuppressant treatment administered for COVID-19 might reactivate the hepatic virus. The high affinity of SARS-CoV-2 spike proteins for cholangiocytes results in a particular type of secondary sclerosing cholangitis. The impact of COVID-19 infection on chronic liver disease patients is significant, especially in cirrhosis, influencing the prognosis and outcome of these patients. [ABSTRACT FROM AUTHOR]

Introduction: Gut microbiota is not only a taxonomic biologic ecosystem but is also involved in human intestinal and extra-intestinal functions such as immune system modulation, nutrient absorption and digestion, as well as metabolism regulation. The latter is strictly linked to non-alcoholic fatty liver disease (NAFLD) pathophysiology. Materials and methods: We reviewed the literature on the definition of gut microbiota, the concepts of "dysbiosis" and "eubiosis", their role in NAFLD pathogenesis, and the data on fecal microbiota transplantation (FMT) in these patients. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, eubiosis, dysbiosis, bile acids, NAFLD, and FMT. Results: Gut microbiota qualitative and quantitative composition is different in healthy subjects vs. NALFD patients. This dysbiosis is associated with and involved in NAFLD pathogenesis and evolution to non-acoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). In detail, microbial-driven metabolism of bile acids (BAs) and interaction with hepatic and intestinal farnesoid nuclear X receptor (FXR) have shown a determinant role in liver fat deposition and the development of fibrosis. Over the use of pre- or probiotics, FMT has shown preclinical and initial clinical promising results in NAFLD treatment through re-modulation of microbial dysbiosis. Conclusions: Promising clinical data support a larger investigation of gut microbiota dysbiosis reversion through FMT in NAFLD using randomized clinical trials to design precision-medicine treatments for these patients at different disease stages. [ABSTRACT FROM AUTHOR]

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is the recent nomenclature designation that associates the condition of non-alcoholic fatty liver disease (NAFLD) with metabolic dysfunction. Its diagnosis has been debated in the recent period and is generally associated with a diagnosis of steatosis and at least one pathologic condition among overweight/obesity, type 2 diabetes mellitus, and metabolic dysregulation. Its pathogenesis is defined by a "multiple-hit" model and is associated with alteration or dysbiosis of the gut microbiota. The pathogenic role of dysbiosis of the gut microbiota has been investigated in many diseases, including obesity, type 2 diabetes mellitus, and NAFLD. However, only a few works correlate it with MAFLD, although common pathogenetic links to these diseases are suspected. This review underlines the most recurrent changes in the gut microbiota of patients with MAFLD, while also evidencing possible pathogenetic links. [ABSTRACT FROM AUTHOR]

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics. [ABSTRACT FROM AUTHOR]

Liver disease is one of the leading public health problems faced by healthcare practitioners regularly. As such, there has been a search for an inexpensive, readily available, non-invasive marker to aid in monitoring and prognosticating hepatic disorders. Recently, red blood cell distribution width (RDW) has been found to be associated with various inflammatory conditions with implications for its use as a potential marker for assessing disease progression and prognosis in multiple conditions. Multiple factors effect red blood cell production whereby a dysfunction in any process can lead to anisocytosis. Furthermore, a chronic inflammatory state leads to increased oxidative stress and produces inflammatory cytokines causing dysregulation and increased intracellular uptake and use of both iron and vitamin B12, which leads to a reduction in erythropoiesis causing an increase in RDW. This literature review reviews in-depth pathophysiology that may lead to an increase in RDW and its potential correlation with chronic liver diseases, including hepatitis B, hepatitis C, hepatitis E, non-alcoholic fatty liver disease, autoimmune hepatitis, primary biliary cirrhosis, and hepatocellular carcinoma. In our review, we examine the use of RDW as a prognostic and predictive marker for hepatic injury and chronic liver disease. [ABSTRACT FROM AUTHOR]

Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the Usp8 and Usp48 loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis with insulin resistance, oxidative stress, lipotoxicity, adipokine secretion by fat cells, endotoxins (lipopolysaccharides) released by gut microbiota, and endoplasmic reticulum stress. Together, these factors promote NAFLD progression from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually end-stage liver diseases in a proportion of cases. Hepatic fibrosis and carcinogenesis often progress together, sharing inflammatory pathways. However, NASH can lead to hepatocarcinogenesis with minimal inflammation or fibrosis. In such instances, insulin resistance, oxidative stress, and lipotoxicity can directly lead to liver carcinogenesis through genetic and epigenetic alterations. Transforming growth factor (TGF)-β signaling is implicated in hepatic fibrogenesis and carcinogenesis. TGF-β type I receptor (TβRI) and activated-Ras/c-Jun-N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3 to create two phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TβRI/pSmad3C signaling terminates cell proliferation, while constitutive Ras activation and JNK-mediated pSmad3L promote hepatocyte proliferation and carcinogenesis. The pSmad3L signaling pathway also antagonizes cytostatic pSmad3C signaling. This review addresses TGF-β/Smad signaling in hepatic carcinogenesis complicating NASH. We also discuss Smad phospho-isoforms as biomarkers predicting HCC in NASH patients with or without cirrhosis. [ABSTRACT FROM AUTHOR]

Objective. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The pathogenesis of NAFLD is complex and multifactorial. Clinical studies have shown that alterations in the gut microbiota play a key role in NAFLD. The purpose of this study was to analyze the effect of probiotic supplementation on the treatment of NAFLD patients based on various indicators. Methods. We conducted a meta-analysis investigating the relationship between NAFLD and probiotic supplementation. Embase, PubMed, and Web of Science databases were searched by computer, and then, eligible studies were identified. Finally, a total of high-quality randomized controlled trials were selected involving 1403 participants. Meta-analysis was performed using the RevMan 5.3 software which was systematically searched for works published through Dec. 1, 2021, in the present study. Results. The meta-analysis results showed that the probiotics supplementation improved hepatocyte injury and significantly reduced the level of ALT (P = 0.00001), AST (P = 0.0009), GGT (P = 0.04), TG (P = 0.01), LDL-C (P = 0.0005), HDL-C (P = 0.0002), insulin (P = 0.003), IR (P = 0.03), BMI (P = 0.03), TNF-α (P = 0.03), and CRP (P = 0.02), respectively, in NAFLD patients. Conclusion. The present study suggests that probiotics therapy may improve liver enzyme levels, regulated lipid metabolism, reduced insulin resistance, and improved inflammation in NAFLD patients. It supports the potential role of probiotics supplementation in the treatment of NAFLD. [ABSTRACT FROM AUTHOR]