Alanine and aspartate aminotransferase and glutamine-cycling pathway:Their roles in pathogenesis of metabolic syndrome

Although new research technologies are constantly used to look either for genes or biomarkers in the prediction of metabolic syndrome(MS),the pathogenesis and pathophysiology of this complex disease remains a major challenge.Interestingly,Cheng et al recently investigated possible pathways underlying MS by high-throughput metabolite profiling in two large and well characterized community-based cohorts.The authors explored by liquid chromatography and mass spectrometry the plasma concentrations of 45 distinct metabolites and examined their relation to cardiometabolic risk,and observed that metabolic risk factors such as obesity,insulin resistance(IR),high blood pressure,and dyslipidemia were associated with several metabolites,including branched-chain amino acids,other hydrophobic amino acids,tryptophan breakdown products,and nucleotide metabolites.In addition,the authors found a significant association of IR traits with glutamine,glutamate and the glutamineto-glutamate ratio.These data provide new insight into the pathogenesis of MS-associated phenotypes and introduce a crucial role of glutamine-cycling pathway as prominently involved in the development of metabolic risk.We consider that the hypothesis about the role of abnormal glutamate metabolism in the pathogenesis of the MS is certainly challenging and suggests the critical role of the liver in the global metabolic modulation as glutamate metabolism is linked with aminotransferase reactions.We discuss here the critical role of the "liver metabolism" in the pathogenesis of the MS and IR,and postulate that before fatty liver develops,abnormal levels of liver enzymes,such as alanine and aspartate aminotransferases might reflect high levels of hepatic transamination of amino acids in the liver.

Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system

Genome-wide association studies of complex diseases,including nonalcoholic fatty liver disease(NAFLD),have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits—a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies.We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD.We used information retrieved from large public National Health and Nutrition Examination Surveys,Genome-wide association studies,and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits.Next,we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis,and genes that modulate hematological-related traits—specifically platelet count.We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets.Genes associated with platelet count are most highly expressed in the liver,followed by the pancreas,heart,and muscle.Conversely,genes associated with NAFLD presented high expression levels in the brain,lung,spleen,and colon.Functional mapping,gene prioritization,and functional analysis of the most significant loci(P<1×10-8)revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways.In conclusion,variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits,particularly platelet count.Likewise,significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways.Hence,this approach yields novel mechanistic insights into NAFLD pathogenesis.

Liver enzymes,metabolomics and genome-wide association studies:From systems biology to the personalized medicine

For several decades,serum levels of alanine(ALT) and aspartate(AST) aminotransferases have been regarded as markers of liver injury,including a wide range of etiologies from viral hepatitis to fatty liver.The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes,coronary heart disease,atherothrombotic risk profile,and overall risk of metabolic disease.Therefore,it is plausible to suggest that aminotransferases are surrogate biomarkers of "liver metabolic functioning" beyond the classical concept of liver cellular damage,as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function.In this study,we summarize the background information and recent findings on the biological role of ALT and AST,and review the knowledge gained from the application of genome-wide approaches and "omics" technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions.Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes,which suggest that regulation of aminotransferase activity is a complex and highly regulated trait.Finally,links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.

Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.

Tackling the complexity of nonalcoholic steatohepatitis treatment:challenges and opportunities based on systems biology and machine learning approaches

Nonalcoholic fatty liver disease(NAFLD)is regarded as the most frequent cause of chronic liver damage(1,2).The natural history of the disease presents a complex scenario of potential progression into severe clinical outcomes,including nonalcoholic steatohepatitis(NASH),NASH-fibrosis,cirrhosis,and hepatocellular carcinoma(1,2).In addition,NAFLD is closely associated with comorbidities of the metabolic syndrome(MetS),including type 2 diabetes,obesity,arterial hypertension,and dyslipidemia,which together aggravate the morbidity and mortality associated with the disease.

PNPLA3,the triacylglycerol synthesis/hydrolysis/storage dilemma,and nonalcoholic fatty liver disease

Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease(NAFLD).However,the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3(PNPLA3,also known as adiponutrin).A nonsynonymous single nucleotide polymorphism in PNPLA3(rs738409 C/G,a coding variant that encodes an amino acid substitution I148M) is significantly associated with fatty liver and histological disease severity,not only in adults but also in children.Nevertheless,how PNPLA3 influences the biology of fatty liver disease is still an open question.A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function.We revise here the published data about the role of the I148M variant in lipogenesis/lipolysis,and suggest putative areas of future research.For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation,and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3' UTR region(hsa-miR-769-3p and hsa-miR-516a-3p).In addition,interesting unanswered questions remain to be explored.For example,PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity,and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element,corroborated by the DNase Ⅰ hypersensitivity site peak.Finally,an interaction between PNPLA3 and glycerol3-phosphate acyltransferase 2 is suggested by data miming.

Nonalcoholic steatohepatitis pharmacotherapy and predictors of response: dual role of aminotransferases as biosensors of metabolism and biomarkers of histological improvement

Nonalcoholic steatohepatitis (NASH)—the severe histological form of nonalcoholic fatty liver disease (NAFLD)—is regarded as a major health problem worldwide (1,2). The disease can progress to liver cirrhosis and eventually to hepatocellular carcinoma (1,3). Treatment of NASH and NASH-fibrosis is thus increasingly being given priority in the clinical field. Yet, these efforts face challenges not only related to the design and validation of novel pharmacological agents, but also to the need to optimize treatment options as well as improve access to therapies. In fact, while many drugs are currently being tested for safety and efifcacy, only a few approved options for the treatment of NASH presently exist (4,5). It is thus expected that, in the near future, emphasis will be given to selecting the right drug for treating NASH patients from a wide spectrum of treatment choices. Hence, identiifcation of early predictors of treatment response represents an unmet and relevant need.

Repurposing drugs to target nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis(NASH) and NASH-fibrosis-the severe histological forms. Over the past decade,tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases(phase 1 and 2),which involve testing tolerability, therapeutic action, and pharmacological issues.It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.

Liver tissue microbiota in nonalcoholic liver disease:a change in the paradigm of host-bacterial interactions

Nonalcoholic fatty liver disease(NAFLD)pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors,the genetic variance of the nuclear and mitochondrial genome,associated phenotypic traits,and the yet not fully explored interactions with epigenetic and other environmental factors,including the microbiome.Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD,the precise mechanisms that explain the variability of the histological phenotypes are not fully understood.Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis(NASH)provided clues on the role of the fecal microbiome in the disease pathogenesis.Nevertheless,the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity,including liver inflammation,ballooning of hepatocytes,and fibrosis.The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein.Therefore,not only microbes would become entrapped in the complex liver anatomy but,more importantly,bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response.Hence,the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a“gut-centric”to a“liver-centric”approach.Here,we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH.Besides,we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.