RESUMEN
OBJECTIVES: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. METHODS: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe-/- and Apoe-/-/Hmgcr KI mice. RESULTS: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe-/-/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe-/-/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe-/-/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. CONCLUSIONS: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
Asunto(s)
Aterosclerosis , Mielopoyesis , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Colesterol , Femenino , Masculino , RatonesRESUMEN
The neuropeptide Y (NPY) system has been recognized as one of the most critical molecules in the regulation of energy homeostasis and glucose metabolism. Abnormal levels of NPY have been shown to contribute to the development of metabolic disorders including obesity, cardiovascular diseases, and diabetes. NPY centrally promotes feeding and reduces energy expenditure, while the other family members, peptide YY (PYY) and pancreatic polypeptide (PP), mediate satiety. New evidence has uncovered additional functions for these peptides that go beyond energy expenditure and appetite regulation, indicating a more extensive function in controlling other physiological functions. In this review, we will discuss the role of the NPY system in the regulation of pancreatic ß-cell function and its therapeutic implications for diabetes.
Asunto(s)
Células Secretoras de Insulina/metabolismo , Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Arginina/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Humanos , Terapia Molecular Dirigida , Receptores de Neuropéptido Y/antagonistas & inhibidoresRESUMEN
BACKGROUND: Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones-osteocalcin, lipocalin 2, and sclerostin-are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation is one of the hallmarks of cardiometabolic diseases and a major contributor to disease progression. Novel evidence also implicates important roles of bone-derived hormones in the regulation of chronic inflammation. SCOPE OF REVIEW: In this review, we provide a detailed overview of the physiological and pathological roles of osteocalcin, lipocalin 2, and sclerostin in cardiometabolic health regulation and disease development, with a focus on the modulation of chronic inflammation. MAJOR CONCLUSIONS: Evidence supports that osteocalcin has a protective role in cardiometabolic health, and an increase of lipocalin 2 contributes to the development of cardiometabolic diseases partly via pro-inflammatory effects. The roles of sclerostin appear to be complicated: It exerts pro-adiposity and pro-insulin resistance effects in type 2 diabetes and has an anti-calcification effect during cardiovascular disease. A better understanding of the actions of these bone-derived hormones in the pathophysiology of cardiometabolic diseases will provide crucial insights to help further research develop new therapeutic strategies to treat these diseases.