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UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders.Cell Metabolism Aug 2023Inflammation is closely associated with obesity and related metabolic disorders. However, its origin during obesity is largely unknown. Here, we report that...
Inflammation is closely associated with obesity and related metabolic disorders. However, its origin during obesity is largely unknown. Here, we report that ubiquitin-conjugating enzyme E2M (UBE2M) is critical to obesity-related inflammation induced by macrophages. In mice with UBE2M-deficient macrophages, obesity, insulin resistance, and hepatic steatosis induced by a high-fat diet are greatly alleviated, an effect related to the decreased proinflammatory activity of macrophages due to reduced IL-1β production. Mechanistically, UBE2M deficiency inhibits the neddylation of E3 ubiquitin ligase TRIM21 on K129/134, leading to reduced recruitment and ubiquitination-mediated degradation of E3 ubiquitin ligase VHL. Subsequently, VHL reduces HIF-1α-induced IL-1β production by degrading HIF-1α. Targeting macrophage TRIM21 with Trim21 antisense oligonucleotide-loaded red blood cell extracellular vesicles effectively inhibits obesity-induced inflammation and related metabolic disorders. Thus, our results demonstrate that macrophage UBE2M is essential for obesity-induced inflammation and that TRIM21 is a proof-of-concept target for treating obesity and associated metabolic diseases.
Topics: Mice; Animals; Ubiquitin-Protein Ligases; Ubiquitination; Obesity; Inflammation; Metabolic Diseases
PubMed: 37343564
DOI: 10.1016/j.cmet.2023.05.011 -
Current Problems in Cardiology Feb 2024The correlation between obesity, type 2 diabetes mellitus (DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) is an escalating and widely acknowledged... (Review)
Review
The correlation between obesity, type 2 diabetes mellitus (DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) is an escalating and widely acknowledged epidemic in industrialized nations. Recently, this complex web of interrelated health conditions has been collectively defined as the Cardiovascular-Kidney-Metabolic (CKM) syndrome by the American Heart Association (AHA). The molecular mechanisms underlying CKM disease contain a spectrum of interconnected factors, including hyperglycemia, insulin resistance, heightened activity of the renin-angiotensin-aldosterone system (RAAS), the generation of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, abnormalities in calcium handling, malfunctioning of mitochondria and impaired energy production, as well as persistent chronic inflammation. Addressing their prevention, management, and treatment is of paramount importance to promote better patient health outcomes. The objective of this review is to provide a comprehensive and critical examination of the current state-of-the-art regarding the recently defined CKM syndrome. This includes an exploration of epidemiological evidence establishing connections between cardio-renal-metabolic diseases, an examination of the underlying pathophysiological mechanisms, and a comprehensive overview of existing treatment modalities.
Topics: Humans; Diabetes Mellitus, Type 2; Metabolic Syndrome; Kidney; Insulin Resistance; Obesity
PubMed: 38103820
DOI: 10.1016/j.cpcardiol.2023.102344 -
Cardiovascular Diabetology Jul 2023Type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), are recognized among the most disruptive public health issues of the current... (Review)
Review
Type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), are recognized among the most disruptive public health issues of the current century. A large body of evidence from epidemiological and clinical research supports the existence of a strong interconnection between these conditions, such that the unifying term cardio-metabolic-renal (CMR) disease has been defined. This coexistence has remarkable epidemiological, pathophysiologic, and prognostic implications. The mechanisms of hyperglycemia-induced damage to the cardio-renal system are well validated, as are those that tie cardiac and renal disease together. Yet, it remains controversial how and to what extent CVD and CKD can promote metabolic dysregulation. The aim of this review is to recapitulate the epidemiology of the CMR connections; to discuss the well-established, as well as the putative and emerging mechanisms implicated in the interplay among these three entities; and to provide a pathophysiological background for an integrated therapeutic intervention aiming at interrupting this vicious crosstalks.
Topics: Humans; Diabetes Mellitus, Type 2; Cardio-Renal Syndrome; Kidney; Cardiovascular Diseases; Renal Insufficiency, Chronic; Metabolic Diseases
PubMed: 37525273
DOI: 10.1186/s12933-023-01937-x -
Gut Mar 2024Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic liver disease globally and is currently estimated to affect up to 38% of the global... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic liver disease globally and is currently estimated to affect up to 38% of the global adult population. NAFLD is a multisystem disease where systemic insulin resistance and related metabolic dysfunction play a pathogenic role in the development of NAFLD and its most relevant liver-related morbidities (cirrhosis, liver failure and hepatocellular carcinoma) and extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain types of extrahepatic cancers. In 2023, three large multinational liver associations proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) should replace the term NAFLD; the name chosen to replace non-alcoholic steatohepatitis was metabolic dysfunction-associated steatohepatitis (MASH). Emerging epidemiological evidence suggests an excellent concordance rate between NAFLD and MASLD definitions-that is, ~99% of individuals with NAFLD meet MASLD criteria. In this narrative review, we provide an overview of the literature on (a) the recent epidemiological data on MASLD and the risk of developing CVD and malignant complications, (b) the underlying mechanisms by which MASLD (and factors strongly linked with MASLD) may increase the risk of these extrahepatic complications and (c) the diagnosis and assessment of CVD risk and potential treatments to reduce CVD risk in people with MASLD or MASH.
Topics: Adult; Humans; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Metabolic Diseases; Cardiovascular Diseases; Liver Neoplasms
PubMed: 38228377
DOI: 10.1136/gutjnl-2023-330595 -
Journal of Hepatology Dec 2023While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of... (Review)
Review
While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of the direct and indirect effects of endocrine dysregulation on the severity of MASLD, with strong evidence that low levels of growth hormone, sex hormones, and thyroid hormone promote the development and progression of disease. The impact of steroid hormones, e.g. cortisol and dehydroepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and management of non-insulin endocrine axes is essential in the evaluation and management of MASLD. Multiple therapeutic options have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in MASH.
Topics: Humans; Insulin Resistance; Metabolic Diseases; Fatty Liver; Adipocytes
PubMed: 37730124
DOI: 10.1016/j.jhep.2023.08.030 -
Gut Feb 2024We explored clinical implications of the new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing its prevalence and associated...
OBJECTIVE
We explored clinical implications of the new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing its prevalence and associated cardiovascular disease (CVD) risk.
DESIGN
From nationwide health screening data, we identified 9 775 066 adults aged 20-79 who underwent health examination in 2009. Participants were categorised into four mutually exclusive groups: (1) MASLD; (2) MASLD with increased alcohol intake (MetALD); (3) MASLD with other combined aetiology (the three collectively referred to as MASLD/related steatotic liver disease (SLD)); and (4) no MASLD/related SLD. SLD was determined by fatty liver index ≥30. The primary outcome was CVD event, defined as a composite of myocardial infarction, ischaemic stroke, heart failure or cardiovascular death.
RESULTS
The prevalence of MASLD, MetALD and MASLD with other combined aetiology was 27.5%, 4.4% and 1.5%, respectively. A total of 8 808 494 participants without prior CVD were followed up for a median of 12.3 years, during which 272 863 CVD events occurred. The cumulative incidence and multivariable-adjusted risk of CVD were higher in participants with MASLD/related SLD than in those without (HR 1.38 (95% CI 1.37 to 1.39)). Multivariable-adjusted HR (95% CI) of CVD events was 1.39 (1.38 to 1.40) for MASLD, 1.28 (1.26 to 1.30) for MetALD and 1.30 (1.26 to 1.34) for MASLD with other combined aetiology compared to the absence of any of these conditions. CVD risk was also higher in participants with metabolic dysfunction-associated fatty liver disease or non-alcoholic fatty liver disease than in those without the respective condition.
CONCLUSION
Over one-third of Korean adults have MASLD/related SLD and bear a high CVD risk.
Topics: Adult; Humans; Cardiovascular Diseases; Brain Ischemia; Stroke; Metabolic Diseases; Non-alcoholic Fatty Liver Disease
PubMed: 37907259
DOI: 10.1136/gutjnl-2023-331003 -
International Journal of Obesity (2005) Jul 2023A bidirectional relationship exists between adipose tissue metabolism and iron regulation. Total body fat, fat distribution and exercise influence iron status and... (Review)
Review
A bidirectional relationship exists between adipose tissue metabolism and iron regulation. Total body fat, fat distribution and exercise influence iron status and components of the iron-regulatory pathway, including hepcidin and erythroferrone. Conversely, whole body and tissue iron stores associate with fat mass and distribution and glucose and lipid metabolism in adipose tissue, liver, and muscle. Manipulation of the iron-regulatory proteins erythroferrone and erythropoietin affects glucose and lipid metabolism. Several lines of evidence suggest that iron accumulation and metabolism may play a role in the development of metabolic diseases including obesity, type 2 diabetes, hyperlipidaemia and non-alcoholic fatty liver disease. In this review we summarise the current understanding of the relationship between iron homoeostasis and metabolic disease.
Topics: Humans; Glucose; Iron; Diabetes Mellitus, Type 2; Obesity; Liver; Lipid Metabolism
PubMed: 37029208
DOI: 10.1038/s41366-023-01299-0 -
Cell Metabolism Sep 2023The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent... (Review)
Review
The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.
Topics: Humans; Incretins; Diabetes Mellitus; Weight Loss; Hyperglycemia; Body Weight; Receptors, G-Protein-Coupled
PubMed: 37591245
DOI: 10.1016/j.cmet.2023.07.010 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Heart Failure; Metabolic Diseases; Stroke Volume
PubMed: 37622676
DOI: 10.1056/NEJMe2309294 -
Nature Human Behaviour Aug 2023Human longevity correlates with socio-economic status, and there is evidence that educational attainment increases human lifespan. However, to inform meaningful health...
Human longevity correlates with socio-economic status, and there is evidence that educational attainment increases human lifespan. However, to inform meaningful health policies, we need fine-grained causal evidence on which dimensions of socio-economic status affect longevity and the mediating roles of modifiable factors such as lifestyle and disease. Here we performed two-sample Mendelian randomization analyses applying genetic instruments of education, income and occupation (n = 248,847 to 1,131,881) to estimate their causal effects and consequences on parental lifespan and self-longevity (n = 28,967 to 1,012,240) from the largest available genome-wide association studies in populations of European ancestry. Each 4.20 years of additional educational attainment were causally associated with a 3.23-year-longer parental lifespan independently of income and occupation and were causally associated with 30-59% higher odds of self-longevity, suggesting that education was the primary determinant. By contrast, each one-standard-deviation-higher income and one-point-higher occupation was causally associated with 3.06-year-longer and 1.29-year-longer parental lifespans, respectively, but not independently of the other socio-economic indicators. We found no evidence for causal effects of income or occupation on self-longevity. Mediation analyses conducted in predominantly European-descent individuals through two-step Mendelian randomization suggested that among 59 candidates, cigarettes per day, body mass index, waist-to-hip ratio, hypertension, coronary heart disease, myocardial infarction, stroke, Alzheimer's disease, type 2 diabetes, heart failure and lung cancer individually played substantial mediating roles (proportion mediated, >10%) in the effect of education on specific longevity outcomes. These findings inform interventions for remediating longevity disparities attributable to socio-economic inequality.
Topics: Humans; Longevity; Diabetes Mellitus, Type 2; Mendelian Randomization Analysis; Genome-Wide Association Study; European People; Social Class
PubMed: 37386110
DOI: 10.1038/s41562-023-01646-1