Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation.

Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis.

Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques.

PRDM16 deficiency in vascular smooth muscle cells aggravates abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain-containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown.

BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. BAF60c, a unique subunit of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, is critical for cardiac and skeletal myogenesis, yet little is known about its function in the vasculature and, specifically, in AAA pathogenesis. Here, we found that BAF60c was downregulated in human and mouse AAA tissues, with primary staining to vascular smooth muscle cells (VSMCs), confirmed by single-cell RNA-sequencing.

Induction of glutathione biosynthesis by glycine-based treatment mitigates atherosclerosis.

Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties.

Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647).

Type 2 diabetes sex-specific effects associated with E167K coding variant in .

The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene () is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts.

Inhibition of a Novel CLK1-THRAP3-PPARγ Axis Improves Insulin Sensitivity.

Increasing energy expenditure by promoting "browning" in adipose tissues is a promising strategy to prevent obesity and associated diabetes. To uncover potential targets of cold exposure, which induces energy expenditure, we performed phosphoproteomics profiling in brown adipose tissue of mice housed in mild cold environment at 16°C. We identified CDC2-like kinase 1 (CLK1) as one of the kinases that were significantly downregulated by mild cold exposure.

Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis.

Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT.

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown.

Single-Cell Transcriptomics Reveals Endothelial Plasticity During Diabetic Atherogenesis.

Atherosclerosis is the leading cause of cardiovascular diseases, which is also the primary cause of mortality among diabetic patients. Endothelial cell (EC) dysfunction is a critical early step in the development of atherosclerosis and aggravated in the presence of concurrent diabetes. Although the heterogeneity of the organ-specific ECs has been systematically analyzed at the single-cell level in healthy conditions, their transcriptomic changes in diabetic atherosclerosis remain largely unexplored.

AMPKα2 activation by an energy-independent signal ensures chromosomal stability during mitosis.

AMP-activated protein kinase (AMPK) senses energy status and impacts energy-consuming events by initiating metabolism regulatory signals in cells. Accumulating evidences suggest a role of AMPK in mitosis regulation, but the mechanism of mitotic AMPK activation and function remains elusive. Here we report that AMPKα2, but not AMPKα1, is sequentially phosphorylated and activated by CDK1 and PLK1, which enables AMPKα2 to accurately guide chromosome segregation in mitosis.

Integration of Transformative Platforms for the Discovery of Causative Genes in Cardiovascular Diseases.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Genome-wide association studies (GWAS) are powerful epidemiological tools to find genes and variants associated with cardiovascular diseases while follow-up biological studies allow to better understand the etiology and mechanisms of disease and assign causality. Improved methodologies and reduced costs have allowed wider use of bulk and single-cell RNA sequencing, human-induced pluripotent stem cells, organoids, metabolomics, epigenomics, and novel animal models in conjunction with GWAS.

Krüppel-like factor 14 deletion in myeloid cells accelerates atherosclerotic lesion development.

Aims: Atherosclerosis is the dominant pathologic basis of many cardiovascular diseases. Large genome-wide association studies have identified that single-nucleotide polymorphisms proximal to Krüppel-like factor 14 (KLF14), a member of the zinc finger family of transcription factors, are associated with higher cardiovascular risks. Macrophage dysfunction contributes to atherosclerosis development and has been recognized as a potential therapeutic target for treating many cardiovascular diseases.

KLF11 protects against abdominal aortic aneurysm through inhibition of endothelial cell dysfunction.

Abdominal aortic aneurysm (AAA) is a life-threatening degenerative vascular disease. Endothelial cell (EC) dysfunction is implicated in AAA. Our group recently demonstrated that Krüppel-like factor 11 (KLF11) plays an essential role in maintaining vascular homeostasis, at least partially through inhibition of EC inflammatory activation.

Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2.

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis.

Human apolipoprotein A-II reduces atherosclerosis in knock-in rabbits.

Background And Aims: Apolipoprotein A-II (apoAII) is the second major apolipoprotein of the high-density lipoprotein (HDL) particle, after apoAI. Unlike apoAI, the biological and physiological functions of apoAII are unclear. We aimed to gain insight into the specific roles of apoAII in lipoprotein metabolism and atherosclerosis using a novel rabbit model.

Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome.

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 ().

Genome engineering technologies in rabbits.

The rabbit has been recognized as a valuable model in various biomedical and biological research fields because of its intermediate size and phylogenetic proximity to primates. However, the technology for precise genome manipulations in rabbit has been stalled for decades, severely limiting its applications in biomedical research. Novel genome editing technologies, especially CRISPR/Cas9, have remarkably enhanced precise genome manipulation in rabbits, and shown their superiority and promise for generating rabbit models of human genetic diseases.

BAF60a Deficiency in Vascular Smooth Muscle Cells Prevents Abdominal Aortic Aneurysm by Reducing Inflammation and Extracellular Matrix Degradation.

Objective: Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a-a unique subunit of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex-is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)-specific BAF60a in AAA formation.

Single-cell RNA sequencing reveals the cellular heterogeneity of aneurysmal infrarenal abdominal aorta.

Aims: The artery contains numerous cell types which contribute to multiple vascular diseases. However, the heterogeneity and cellular responses of these vascular cells during abdominal aortic aneurysm (AAA) progression have not been well characterized.

Methods And Results: Single-cell RNA sequencing was performed on the infrarenal abdominal aortas (IAAs) from C57BL/6J mice at Days 7 and 14 post-sham or peri-adventitial elastase-induced AAA.

Suppression of Vascular Macrophage Activation by Nitro-Oleic Acid and its Implication for Abdominal Aortic Aneurysm Therapy.

Purpose: Abdominal aortic aneurysm (AAA) is one of the leading causes of death in the developed world and is currently undertreated due to the complicated nature of the disease. Herein, we aimed to address the therapeutic potential of a novel class of pleiotropic mediators, specifically a new drug candidate, nitro-oleic acid (NO-OA), on AAA, in a well-characterized murine AAA model.

Methods: We generated AAA using a mouse model combining AAV.