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Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology
Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.
Journal Article
Fairy tales from the Brothers Grimm
A collection of fifty-five traditional tales collected by the Grimm brothers features the original black-and-white illustrations by George Cruikshank plus new color illustrations by noted contemporary illustrators.
BOOK
MAFLD: How is it different from NAFLD?
“Metabolic dysfunction-associated fatty liver disease (MAFLD)” is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.
Journal Article
Cytokines: From Clinical Significance to Quantification
Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases. Quantification of cytokines has significant value in both clinical medicine and biology as the levels provide insights into physiological and pathological processes and can be used to aid diagnosis and treatment. Cytokines and their clinical significance are introduced from the perspective of their pro‐ and anti‐inflammatory effects. Factors affecting cytokines quantification in biological fluids, native levels in different body fluids, sample processing and storage conditions, sensitivity to freeze‐thaw, and soluble cytokine receptors are discussed. In addition, recent advances in in vitro and in vivo assays, biosensors based on different signal outputs and intracellular to extracellular protein expression are summarized. Various quantification platforms for high‐sensitivity and reliable measurement of cytokines in different scenarios are discussed, and commercially available cytokine assays are compared. A discussion of challenges in the development and advancement of technologies for cytokine quantification that aim to achieve real‐time multiplex cytokine analysis for point‐of‐care situations applicable for both biomedical research and clinical practice are discussed.
Cytokines are important cellular signaling molecules and immune system mediators. Abnormal cytokine levels may cause cytokine storm and diseases. Consequently, quantification of cytokines is valuable for diseases diagnosisand therapy. The clinical significance of cytokines, factors affecting cytokine quantification, and advances of cytokine detection are summarized, providing a prospective for real‐time quantification of multiplex cytokines in the clinic.
Journal Article
Adding to the confusion in more than just the name
Subsequent years have seen more than 4,000 citations for the two sentinel papers, over 7,000 publications using the MAFLD terminology and definition, and widespread acceptance in clinical practice guidelines including the first by the Asian Pacific Association for the Study of Liver (APASL) [4], the Middle East and North Africa [5], the Chinese Society of Hepatology [6], and many other national societies as well as patient organisations [7]. The fact that the proposal of MASLD has come after four decades highlights the inertia of societies and the importance of innovation and renewal from the grass roots in all scientific disciplines. First and foremost, as suggested by others in the field and patient groups, the term “fatty liver”, when used to describe a liver with fat, is not stigmatising [13,14]. [...]as circulated on social media and from first-hand experience, clinicians know from every day experience that when a patient is told they have MASLD, the first question asked is “what does steatotic liver disease mean,” to which the answer invariably is that you have a “fatty liver”. To be clear, MAFLD is a set of criteria for clinical diagnosis, while steatohepatitis is a histological diagnosis.
Journal Article
The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.
Journal Article
From MAFLD to hepatocellular carcinoma and everything in between
Metabolic (dysfunction) associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease, is the most common cause of chronic liver disease worldwide. Many risk factors contribute to the pathogenesis of MAFLD with metabolic dysregulation being the final arbiter of its development and progression. MAFLD poses a substantial economic burden to societies, which based on current trends is expected to increase over time. Numerous studies have addressed various aspects of MAFLD from its risk associations to its economic and social burden and clinical diagnosis and management, as well as the molecular mechanisms linking MAFLD to end-stage liver disease and hepatocellular carcinoma. This review summarizes current understanding of the pathogenesis of MAFLD and related diseases, particularly liver cancer. Potential therapeutic agents for MAFLD and diagnostic biomarkers are discussed.
Journal Article
Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer’s disease models
Background
Genetic variants and mutations in triggering receptor expressed in myeloid cells (TREM2) are associated with premature and late onset Alzheimer’s disease (AD).
Methods
We developed a panel of monoclonal antibodies, the selected lead of which was avidly shown to bind the extracellular domain of human and murine TREM2.
Results
By engaging membrane-bound TREM2, the selected antibody was shown to promote their cellular proliferation, uptake of oligomeric beta amyloid/apoptotic neurons, and activation in a Syk and Akt dependent manner. The antibody was shown to avidly bind soluble TREM2 in the CSF from AD patients and blunted the proinflammatory program driven by its intracerebral injection. Upon in vivo treatment, the antibody was shown to improve cognitive function in experimental amyloidopathy models and to facilitate plaque-associated microglial coverage and activation.
Conclusion
Thus, we describe a novel monoclonal antibody targeting membrane bound and soluble TREM2, that improves cognitive function by inducing microglial activation and attenuating chronic neuroinflammation.
Journal Article
Animal models of nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatits can take decades to evolve and progress, which limits the quality of longitudinal data. Researchers have, therefore, turned their attention to the development of suitable animal models to test the role of molecules and molecular pathways in the progression of fatty liver formation. This Review discusses the benchmark animal models that recapitulate the pathology and metabolic dysfunction associated with NALFD.
In 1980, Ludwig and colleagues described a series of patients with liver histology characterized by the accumulation of fat and the presence of hepatic necroinflammation in the absence of a history of excessive alcohol consumption. They coined the term nonalcoholic steatohepatitis (NASH), which today is regarded as one of the most common causes of liver disease in affluent countries. NASH is a subset of a larger spectrum of diseases termed fatty liver disease (including alcoholic and nonalcoholic fatty liver disease; AFLD and NAFLD, respectively). NAFLD and NASH are linked to visceral adiposity, insulin resistance, dyslipidemia and type 2 diabetes, and are increasing due to the prevalence of the metabolic syndrome. In this context, research has been undertaken using animals to model human steatosis and NAFLD to NASH disease progression. This Review discusses the prevalent dietary and inflammation-based genetic animal models described in recent years.
Key Points
Hepatic steatosis is associated with the metabolic syndrome
No dietary animal model can fully recapitulate the human steatosis disease process
Genetic models have shown adipose inflammation to drive hepatic steatosis
Cholesterol promotes hepatic inflammation
Journal Article