The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing rapidly worldwide due to the obesity epidemic. Advanced stages of the MAFLD, such as non-alcoholic steatohepatitis (NASH) with advanced fibrosis or cirrhosis are affecting global health. Extracellular vesicles (EVs) are released by all cell types and are important in cell-to-cell communication and maintaining homeostasis, but they also play a role in the pathogenesis of various diseases. EVs contain biological information such as lipids, proteins, messenger RNAs (mRNAs), small RNAs, and DNA, and they act on (distant) target cells. The cargo of EVs is dependent on the type and the state of the releasing cell. EVs have been proposed as biomarkers, prognostic, and even therapeutic agents, also in the context of liver diseases. This review aims to give an overview of the current knowledge on EVs in MAFLD, including the role and interaction of EVs with different cell types in the liver. Several aspects of EVs, including their origin, characteristics, cargo, and functions are reviewed. Moreover, the potential of EVs as targets for the treatment of MAFLD is discussed.

It is generally accepted that eradication of Helicobacter pylori (H. pylori) infection may reduce the risk of the development of gastric cancer. Recommendations for global generalized tests and treat all individuals detected positive for H. pylori infection are currently proposed. However, the bacterium is commensal and harmless for the vast majority of the infected population. Moreover, eradication may have detrimental consequences in several groups of patients. In the present review, the current epidemiological data and recommendations for eradication in connection with the possible beneficial effects of the colonization with H. pylori in diseases such as asthma and allergies or chronic gastro-intestinal disorders such as inflammatory bowel disease and Barrett’ esophagus are presented the problems with increasing antibiotic resistance were also examined. Specific groups of patients where eradication of H. pylori may be necessary and endoscopic surveillance is advised were identified. Finally, based on the paradox of high H. pylori prevalence and low gastric risk as reported for areas of Africa, Asia, South America, and Greece, alternatives that may replace the widespread eradication of H. pylori with equal if not better results and more prudent use of the available financial resources are proposed. Mediterranean diets and alcohol and smoking reduction are among the well documented alternatives.

Nonalcoholic fatty liver disease (NAFLD) is an umbrella definition that describes the ectopic deposition of fat within the liver that occurs in the absence of inciting factors other than the metabolic syndrome and its individual features. NAFLD has a multi-factorial pathogenesis which determines heterogeneous clinical phenotypes and variable natural course spanning from liver-related (steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma) to extrahepatic outcomes (cardio-metabolic and cancer). This narrative review article leverages the key aspects of disease natural history as the background information to discuss studies that may inform strategies to risk-stratify NAFLD patients. Evaluation of hepatic fibrosis with non-invasive tools, including blood-based biomarkers and imaging-based elastometry techniques, seemingly retains the core information useful to predict the heterogeneous outcomes listed above. Additionally, genetic testing and metabolomic profiles may also be utilized to this end. In conclusion, a comprehensive understanding of the variable hepatic, cardio-metabolic and cancer outcomes of NAFLD may enable physicians and researchers to risk-stratify and accurately identify the multilayered prognosis of NAFLD individuals while also defining homogeneous patient subsets to enroll in clinical trials.

Drug-induced liver injury (DILI) is an adverse reaction to drugs and other xenobiotics that can have serious consequences and jeopardise progress in pharmacological therapy. While DILI is predominantly hepatocellular, a non-negligible percentage of patients who present with cholestatic damage. Mixed damage is typically lumped together with cholestatic damage in the literature. Drug-induced cholestasis is often caused by the use of some non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (i.e., amoxicillin-clavulanic acid), statins, and anabolic agents, among others. Drug-associated cholestasis tends to have a more chronic course and mostly affects older population. There is also a genetic predisposition to toxic cholestasis caused by some drugs (amoxicillin-clavulanic acid, statins, etc.). Recently, anatomical alterations of the biliary tract induced by drugs (especially immunotherapy drugs) have been described. Bile duct injury is one of the histopathological findings that have prognostic significance in DILI. A correct differential diagnosis with other causes of cholestasis is mandatory to reach an accurate diagnosis. Ursodexycholic acid, corticosteroids, and replacement therapies have been used as a therapeutic arsenal, although more evidence is needed to establish them as a routine therapeutic management in clinical practice. The breakthrough and validation of biomarkers of cholestasis and bile duct injury is an urgent need for drug development and post-marketing phase.

Mitochondria are present in all mammalian cells except matured red blood cells. Mitochondria consist of several metabolic pathways for glucose, fatty acids, amino acids, and bioenergetic pathways for ATP synthesis, membrane potential, and reactive oxygen production. In the liver, hepatic mitochondria play a key role in hepatic steatosis because mitochondrial metabolism produces acetyl-CoA which is the building block for synthesis of lipids and cholesterol. Mitochondria inner membrane is impermeable of metabolites, reducing equivalents, and small molecules such as phosphate, and sulfate. Thus, mitochondrial shuttles and carriers function as the routes of influx and efflux of these metabolites and molecules across the inner membrane. The signal regulation of these shuttles and mitochondrial enzymes could play a key role in coordinating the mitochondrial metabolism to adapt the cytosolic part of metabolic pathways in liver metabolic stress. Intriguingly, the interaction of mitochondria protein SH3 domain-binding protein 5 (SAB/SH3BP5) and c-Jun N-terminal kinase (JNK) was found as a pivotal role in sustained activation of JNK and phosphorylated-JNK (P-JNK) mediated activation of lipogenic pathway in nutritional excess. Knockout or knockdown of SAB prevented or reversed the hepatic steatosis, inflammation, and fibrosis, and improved metabolic intolerance and energy expenditure. Moreover, blocking the SAB peptide prevents palmitic acid-induced P-JNK interaction with SAB and inhibition of mitochondrial bioenergetics, implying the P-JNK effect on mitochondrial metabolism. This review focuses on the flow of mitochondrial metabolites in metabolic stress conditions and the contribution of mitochondria and mitochondrial stress signals in hepatic steatosis.

The surface of intestinal epithelial cells is covered by the brush border, which consists of densely packed cellular extrusions called microvilli. Until recently, microvilli have not been known to be interconnected. In 2014, a protein complex, called the intermicrovillar adhesion complex (IMAC) which is located at the tips of the microvilli and responsible for the regular spatial organization of the brush border, was identified. Deletion of IMAC components such as cadherin-related family member-2 (CDHR2) in mice resulted in microvillus disorganization and fanning, a structural aberration that is also found in the brush border of patients with inflammatory bowel disease. The etiology of inflammatory bowel disease has been primarily associated with dysfunctional mucosal immunity, but the discovery of the IMAC may encourage theories of an epithelial origin. Here, possible effects of the brush border on the gut barrier function and intestinal inflammation are discussed proposing that the IMAC protects against inflammation through its microvillus cross-linking function.

A high consumption of ultra-processed food (UPF) is a hallmark of Western diets that has been related to increased risk of non-communicable diseases. As an underlying mechanism, UPF may promote non-alcoholic fatty liver disease (NAFLD) which is a key driver of metabolic impairment with extra-hepatic manifestations like type 2 diabetes, cardiovascular disease, chronic kidney disease, and osteoporosis among others. The present review provides an overview of UPF properties that may promote NAFLD and are thus potential targets for reformulation of UPF. Such approaches should address improvements in the quality of carbohydrates and fat, changes in food texture that lower eating rate as well as ingredients that prevent excess caloric intake or avoid dysbiosis and leaky gut syndrome. Promising strategies are enrichment with fiber, prebiotics, phytochemicals, and protein with a concurrent reduction in glycemic load, energy density, saturated fatty acids (FA; SFA), emulsifiers, fructose, and non-caloric sweeteners. Future studies are needed to examine the interactive and protective effects of such modifications in the composition of UPF on prevention and treatment of NAFLD.

Chronic liver diseases (CLDs), which are typically characterized by fibrogenic progression towards liver cirrhosis and related complications eventually leading to organ failure and can also lead to the development of primary liver cancers, represent a major burden for human health on a worldwide basis. Although the present knowledge on the pathogenesis of CLDs progression and primary liver cancers development has remarkably increased in the last decades, critical molecular mediators remain incompletely understood, and approved antifibrotic therapies to efficiently counteract CLDs progression and liver cancer are lacking. In the present review, this study will specifically analyse the putative contribution of SERPINB3, a member of the superfamily of serine-protease inhibitors (SERPINs), which has been shown to exert significant pro-inflammatory and pro-fibrogenic roles in progressive CLDs as well as to be involved in the development of primary liver cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma, and hepatoblastoma.

Zebrafish as a preclinical drug induced liver injury (DILI) model provides multiple advantages ranging from ease of breeding and maintenance, availability of different strains and transgenic fish amenable to study liver function, and highly conserved liver structure and function with the human liver. In this review, the authors have aimed to provide an account of the metabolic enzymes that take roles in drug detoxification in both human and zebrafish in a comparative manner and exemplify several recent models in studying liver functionality. Moreover, the authors emphasize the difficulties associated with studying idiosyncratic DILI in preclinical models and propose that zebrafish could be an important complement to mice in testing functions of genes that are associated with DILI with respect to different drugs in human genome-wide association studies (GWAS) Catalog. Finally, this review highlights the state-of-the-art in the development of novel transgenic reporter strains that can be used to study degree and molecular mechanisms of hepatotoxicity caused by drugs in zebrafish. All of these will help researchers to use effectively the available resources in the zebrafish DILI models, while advocating potential leads that can be taken to provide advancements in a better understanding and treatment of DILI.

Excessive alcohol intake is still among the leading causes of chronic liver diseases. Epidemiological studies suggest that per capita consumption of alcohol from various alcohol beverages e.g., beer, wine, or spirits, differs markedly between different areas of the world. Studies further suggest that different alcoholic beverages may impact the development of alcohol-related liver diseases (ALD) differentially. Specifically, results of several more recent epidemiological studies suggest that consumption of wine and herein especially of red wine may be less harmful in relation to the development of liver diseases than the intake of hard spirits. Results of studies evaluating the effects of beer on the development of ALD in humans are rather contradictory. Here, results of studies assessing the impact of wine, beer, and spirits on the development of ALD as well as possible underlying mechanisms are summarized and discussed.

The formation of metabolic changes is based on many factors. In particular, the infectious theory of the development of metabolic “breakdowns” has not lost its relevance. In this regard, many scientists are investigating the role of various microorganisms in the pathogenesis of metabolic syndrome. The review provides the results of current research on the role of Helicobacter pylori (as one of the most well-known and widespread bacterial pathogens) in the pathogenesis of metabolic syndrome. However, the results of scientific work are sometimes contradictory, which dictates the need for novel further research to clarify the characteristics of the influence Helicobacter pylori on the formation of various components of the metabolic syndrome.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and its death rate is rising faster than that of any other cancer, while we still lack effective treatments. The increasing incidence of liver cancer in western countries is closely associated with the growing prevalence of metabolic dysfunction-associated steatohepatitis (MASH) linked to metabolic diseases. While the contribution of lipids in the progression of MASH pathogenesis and its progression to HCC is well recognized, the specific contribution of cholesterol is subject to controversy. The liver plays a central role in cholesterol metabolism, where the majority of its biosynthesis, storage, excretion, recycling, and conversion into bile acids occur. Moreover, cholesterol is implicated in numerous hepatocyte cellular processes, encompassing endoplasmic reticulum function, formation of lipid microdomains in the plasma membrane, metabolism of lipoproteins, and mitochondrial function and performance. Therefore, it is not surprising that cholesterol plays key roles in initiation, promotion, and survival of HCC cells and there are several lines of evidence pointing to that cancer cells are subverting cholesterol metabolism to foster their proliferation and survival through various mechanisms. This narrative review provides a concise overview of the physiological and pathological roles of cholesterol in the transition from healthy hepatocytes to HCC, in the context of MASH. Gaining further understanding of how hepatic cancer cells disrupt cholesterol homeostasis and how these perturbations impact cancer progression will facilitate the identification of novel and more effective cancer treatment strategies in this complex and devastating disease.

Normal hepatobiliary function depends on an adequate bile flow from the liver through the biliary tree to the gallbladder, where bile is stored and concentrated, and from the gallbladder to the duodenum when it is required for the digestive process. Interruption of this secretory function results in partial or complete cholestasis, which is accompanied by important repercussions due to the lack of bile acids in the intestine and their regurgitation from hepatocytes to blood together with potentially toxic compounds that are normally eliminated in bile. The presence of active and selective transporter proteins located at both poles of the plasma membrane of hepatocytes, cholangiocytes, and epithelial cells of the ileal mucosa, together with the ability of hepatocytes to synthesize bile acids from cholesterol, enables the so-called bile acid enterohepatic circulation, which is essential in liver and gastrointestinal tract physiology. The presence in the ducts of the biliary tree of agents reducing their luminal diameter by external compression or space-occupying obstacles, either in the duct wall or its lumen, can result in total or partial obstructive cholestasis. The clinical impact and management of cholestasis are different depending on the intrahepatic or extrahepatic location of the obstacle. Thus, surgical interventions can often be helpful in removing extrahepatic obstructions and restoring normal bile flow to the duodenum. In contrast, hepatocyte or cholangiocyte damage, either global, restricted to subcellular compartments, or more specifically affecting the elements of the canalicular secretory machinery, may result in hepatocellular cholestasis or cholangiopathies. In these cases, bile flow interruption is usually partial and, except for extremely severe cases when liver transplantation is required, these patients often treated with pharmacological agents, such as ursodeoxycholic acid (UDCA) and rifampicin. The present review gathers updated information on the etiopathogenesis and pathophysiological aspects of different types of cholestasis.

Evaluation of the hepatobiliary function is critical for the clinicians, not only for the diagnosis of a large variety of liver diseases but also in the follow-up and management of some patients, for instance, those with different degrees of cholestasis suffering from a drug-induced liver injury (DILI) or scheduled for liver resection. Currently, the determination of global liver function mainly relies on laboratory tests, clinical scores, and data from images obtained with ultrasonography, computed tomography (CT), or magnetic resonance. Nuclear medicine scanning, displaying either planar or three-dimensional spatial distribution of liver function, is enhanced when using hepatotropic tracers based on classical radioisotopes such as technetium-99m (^99mTc) and with higher resolution using metabolized probes such as those based on monosaccharide derivatives labeled with ¹⁸F. Other cholephilic compounds, and hence selectively secreted into bile, have been proposed to visualize the correct function of the liver parenchyma and the associated secretory machinery. This review aims to summarize the state-of-the-art regarding the techniques and chemical probes available to monitor liver and gallbladder function, in some cases based on imaging techniques reflecting the dynamic of labeled cholephilic compounds.

Worldwide the number of individuals being overweight or obese has dramatically increased during the last decades, which is also associated with a similar dramatic increase of individuals afflicted with metabolic disorders like dyslipidemia, hypertension, and non-alcoholic fatty liver disease (NAFLD). Genetic predisposition may account for some of the increases in body weight and the development of metabolic disorders; however, much is probably also related to the changes in physical activity and dietary pattern. Indeed, results of epidemiological studies suggest that a ‘western-type dietary pattern’ composed of highly processed foods, sweetened foods, and beverages, all adding to a low fiber but high sugar and saturated fat intake, may increase the odd of developing overweight and metabolic disorders. Consumption of sugar, and especially, fructose has repeatedly been discussed to be a key contributor to the development of health disturbances including hypertension, dyslipidemia, insulin resistance as well as NAFLD. However, despite intense research effort, the question if and how (high) dietary fructose intake interferes with human health has not yet been fully answered also as findings are sometimes contradictory. In the present narrative review, results of recent studies assessing the effect of fructose consumption on the development of metabolic disorders including hypertension, dyslipidemia, cardiovascular diseases (CVDs), hyperinsulinemia, and NAFLD as well as underlying molecular mechanisms are reviewed, thereby, aiming to further address the question if (high) fructose intake is a trigger of metabolic diseases.

Hunting for tumoral material in body fluids, traditionally in blood, the so-called liquid biopsy is set to revolutionize the diagnosis and management of oncological patients. However, other biofluids can also be considered as alternative sources of biomarkers to provide clinically valuable information for multiple diseases. This is the case of bile, a fluid produced in the liver, stored in the gallbladder, and excreted to the duodenum, which complex composition is known to change in different pathological conditions. Remarkably, different works have demonstrated that the identification of mutations in bile cell-free DNA (cfDNA) can outperform blood analysis for the early diagnosis of biliopancreatic tumors causing biliary strictures. Here, the literature in which bile has been tested as a liquid biopsy matrix where lipids, metabolites, proteins, and cfDNA among other analytes were measured is reviewed. Moreover, the clinical situations and procedures where bile can be available, discussing the possible applications and limitations of bile analysis are summarized. The scientific relevance and clinical potential of bile harvesting, biobanking, and analysis are put forward. All this evidence supports the value of bile as a liquid biopsy matrix for the management of patients beyond cancer, and perhaps also beyond “blood, sweat, and tears”.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver diseases. Over time, there has been a significant increase in the prevalence of MASLD. It has become one of the leading causes of hepatocellular carcinoma (HCC) in the United States, France, and the United Kingdom. Globally, the incidence of HCC related to MASLD may further increase with the growing prevalence of obesity. Non-alcoholic steatohepatitis (NASH) is an important stage of MASLD, which is more likely to cause cirrhosis and even HCC. And patients with NASH cirrhosis have a much higher incidence of hepatocellular cancer than patients with non-cirrhotic MASLD. As a result, it is critical to investigate the targets of MASLD therapy in HCC. This article reviews therapeutic targets of MASLD, such as farnesoid X receptor (FXR), peroxisome proliferator activated receptor (PPAR), fibroblast growth factor-21 (FGF-21), etc., and introduces the drugs related to these targets and their mechanisms of action in HCC. In addition, the developmental process and pathogenesis of MASLD, as well as risk factors for HCC development, are discussed. These are of great significance for the prevention and treatment of HCC.

The word “Kampo medicine” means the traditional Japanese herbal medicine. Even “natural herb” can cause drug-induced liver injury (DILI). In this review, the characteristics of Kampo medicine-induced liver injury (KMILI) are reported. The main causative herb involved in Kampo medicine is Scutellariae Radix. KMILI is based on certain hypersensitivity reactions. A small amount of Kampo medicine can cause liver injury, and KMILI can develop after a short latency period. The incidence of liver injury related to Scutellariae Radix is about 1%. KMILI is usually mild and not fatal. The latency period usually lasts 4 weeks to 24 weeks. Fatigue and loss of appetite are sometimes observed. Eosinophilia is not frequently observed. All three types of liver injuries are observed in KMILI: cholestatic, hepatocellular, and mixed types. In Japan, lymphocyte transformation test (LTT) has been generally used for the diagnosis of DILI; however, LTT is likely to yield false-positive result for Kampo medicines, and thus often leads to misdiagnosis in many cases. Recently, researchers reported that a specific human leukocyte antigen (HLA) genotype is possibly associated with KMILI. This hypothesis needs to be examined further. Although Kampo medicine is based on rich knowledge and experience that occurred over a period of thousands of years, much is still unknown about KMILI.