Fenofibrate-promoted hepatomegaly and liver regeneration are PPAR-dependent and partially related to the YAP pathway.

Fenofibrate, a peroxisome proliferator-activated receptor (PPAR) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear.

B3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity.

Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown.

Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity.

The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in the metabolism of neurosteroids. The antiepileptic drug phenytoin (PHT) has been observed to induce neuronal side effects in patients, which could be attributed to its induction of CYP expression and testosterone (TES) metabolism in the hippocampus. While pregnane X receptor (PXR) is widely known for its regulatory function of CYPs in the liver, we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, has differential effects on CYP expression in the liver and hippocampus.

Diabetes Mellitus to Accelerated Atherosclerosis: Shared Cellular and Molecular Mechanisms in Glucose and Lipid Metabolism.

Diabetes is one of the critical independent risk factors for the progression of cardiovascular disease, and the underlying mechanism regarding this association remains poorly understood. Hence, it is urgent to decipher the fundamental pathophysiology and consequently provide new insights into the identification of innovative therapeutic targets for diabetic atherosclerosis. It is now appreciated that different cell types are heavily involved in the progress of diabetic atherosclerosis, including endothelial cells, macrophages, vascular smooth muscle cells, dependence on altered metabolic pathways, intracellular lipids, and high glucose.

[The role of inflammation in heart failure with preserved ejection fraction].

Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterized by left ventricular diastolic dysfunction with preserved ejection fraction. With the aging of the population and the increasing prevalence of metabolic diseases, such as hypertension, obesity and diabetes, the prevalence of HFpEF is increasing. Compared with heart failure with reduced ejection fraction (HFrEF), conventional anti-heart failure drugs failed to reduce the mortality in HFpEF due to the complex pathophysiological mechanism and multiple comorbidities of HFpEF.

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function.

Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored.

A time-series minimally invasive transverse aortic constriction mouse model for pressure overload-induced cardiac remodeling and heart failure.

Transverse aortic constriction (TAC) is a widely-used animal model for pressure overload-induced cardiac hypertrophy and heart failure (HF). The severity of TAC-induced adverse cardiac remodeling is correlated to the degree and duration of aorta constriction. Most studies of TAC are performed with a 27-gauge needle, which is easy to cause a tremendous left ventricular overload and leads to a rapid HF, but it is accompanied by higher mortality attributed to tighter aortic arch constriction.

Peroxisome Proliferator-Activated Receptor α Attenuates Hypertensive Vascular Remodeling by Protecting Vascular Smooth Muscle Cells from Angiotensin II-Induced ROS Production.

Vascular remodeling is the fundamental basis for hypertensive disease, in which vascular smooth muscle cell (VSMC) dysfunction plays an essential role. Previous studies suggest that the activation of peroxisome proliferator-activated receptor α (PPARα) by fibrate drugs has cardiovascular benefits independent of the lipid-lowering effects. However, the underlying mechanism remains incompletely understood.

Myeloid peroxisome proliferator-activated receptor α deficiency accelerates liver regeneration via IL-6/STAT3 pathway after 2/3 partial hepatectomy in mice.

Background: Liver regeneration is a fundamental process for sustained body homeostasis and liver function recovery after injury. Emerging evidence demonstrates that myeloid cells play a critical role in liver regeneration by secreting cytokines and growth factors. Peroxisome proliferator-activated receptor α (PPARα), the target of clinical lipid-lowering fibrate drugs, regulates cell metabolism, proliferation, and survival.

Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis.

Background And Aims: Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH.

Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway.

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor abundantly expressed in liver. PPARα activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARα, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARα on drug-induced liver injury remains obscure.

The role of hypoxia-inducible factors in cardiovascular diseases.

Cardiovascular diseases are the leading cause of death worldwide. During the development of cardiovascular diseases, hypoxia plays a crucial role. Hypoxia-inducible factors (HIFs) are the key transcription factors for adaptive hypoxic responses, which orchestrate the transcription of numerous genes involved in angiogenesis, erythropoiesis, glycolytic metabolism, inflammation, and so on.

Vascular Stem/Progenitor Cells in Vessel Injury and Repair.

Vascular repair upon vessel injury is essential for the maintenance of arterial homeostasis and function. Stem/progenitor cells were demonstrated to play a crucial role in regeneration and replenishment of damaged vascular cells during vascular repair. Previous studies revealed that myeloid stem/progenitor cells were the main sources of tissue regeneration after vascular injury.

Inhibition of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice.

Neutrophil infiltration plays an important role in the initiation and development of abdominal aortic aneurysm (AAA). Recent studies suggested that neutrophils could release neutrophil extracellular traps (NETs), leading to tissue injury in cardiovascular diseases. However, the role of NETs in AAA is elusive.

YAP-TEAD mediates PPAR α-induced hepatomegaly and liver regeneration in mice.

Background And Aims: Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.

Approach And Results: In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice.

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells.

Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice ( ) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptosis induced by angiotensin (Ang) II and hydrogen peroxide, and increased the migration of Ang II-challenged cells.

Cardiomyocyte peroxisome proliferator-activated receptor α is essential for energy metabolism and extracellular matrix homeostasis during pressure overload-induced cardiac remodeling.

Peroxisome proliferator-activated receptor α (PPARα), a ligand-activated nuclear receptor critical for systemic lipid homeostasis, has been shown closely related to cardiac remodeling. However, the roles of cardiomyocyte PPARα in pressure overload-induced cardiac remodeling remains unclear because of lacking a cardiomyocyte-specific Ppara-deficient (Ppara) mouse model. This study aimed to determine the specific role of cardiomyocyte PPARα in transverse aortic constriction (TAC)-induced cardiac remodeling using an inducible Ppara mouse model.

Serum Adropin as a Potential Biomarker for Predicting the Development of Type 2 Diabetes Mellitus in Individuals With Metabolic Dysfunction-Associated Fatty Liver Disease.

Adropin, a peptide translated from the (), was mainly expressed in the liver and was a regulator in metabolic and energy homeostasis. This study aims to investigate the correlation between adropin and histological characteristics of the liver, and the clinical relevance of adropin in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). A total of 62 subjects, including 32 healthy controls and 30 MAFLD patients, were enrolled in this case-control study.

Hypoxia inducible factor 1α in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment.

The process of vascular remodeling is associated with increased hypoxia. However, the contribution of hypoxia-inducible factor 1α (HIF1α), the key transcription factor mediating cellular hypoxic responses, to vascular remodeling is established, but not completely understood. In the angiotensin II (Ang II)-induced vascular remodeling model, HIF1α was increased and activated in vascular smooth muscle cells (VSMCs).

Hepatocyte peroxisome proliferator-activated receptor α regulates bile acid synthesis and transport.

Peroxisome proliferator-activated receptor alpha (PPARα) controls lipid homeostasis through regulation of lipid transport and catabolism. PPARα activators are clinically used for hyperlipidemia treatment. The role of PPARα in bile acid (BA) homeostasis is beginning to emerge.

Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis.

Objective: The aim of this study was to investigate whether the nuclear receptor farnesoid X receptor (FXR) could regulate FNDC5/Irisin expression and the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice.

Methods And Results: We treated primary human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonist (CDCA, GW4064, and ivermectin). FNDC5 expression was highly induced by CDCA and GW4064 in hepatocytes, HepG2 cells, and the circulating level of Irisin increased in Rhesus macaques.

DKK3 (Dikkopf-3) Transdifferentiates Fibroblasts Into Functional Endothelial Cells-Brief Report.

Objective- To determine the role of a cytokine-like protein DKK3 (dikkopf-3) in directly transdifferentiating fibroblasts into endothelial cells (ECs) and the underlying mechanisms. Approach and Results- DKK3 overexpression in human fibroblasts under defined conditions for 4 days led to a notable change in cell morphology and progenitor gene expression. It was revealed that these cells went through mesenchymal-to-epithelial transition and subsequently expressed KDR (kinase insert domain receptor) at high levels.

Interleukin-17A-mediated alleviation of cortical astrocyte ischemic injuries affected the neurological outcome of mice with ischemic stroke.

We previously reported that astrocytes are the main sources of interleukin (IL)-17A production that could aggravate neuronal injuries in ischemic stroke. However, the effects of IL-17A on ischemic astrocytes themselves and the underlying molecular mechanism are still unclear. In this study, we found that recombinant mouse (rm) IL-17A could significantly (P < 0.