Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes.

Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes.

The Emerging Role of SIRT7 in Glucose and Lipid Metabolism.

Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6.

Hypoxia causes pancreatic β-cell dysfunction and impairs insulin secretion by activating the transcriptional repressor BHLHE40.

Hypoxia can occur in pancreatic β-cells in type 2 diabetes. Although hypoxia exerts deleterious effects on β-cell function, the associated mechanisms are largely unknown. Here, we show that the transcriptional repressor basic helix-loop-helix family member e40 (BHLHE40) is highly induced in hypoxic mouse and human β-cells and suppresses insulin secretion.

YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer.

Tumor-initiating cells are major drivers of chemoresistance and attractive targets for cancer therapy, however, their identity in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a cellular subpopulation with partial epithelial-mesenchymal transition (EMT)-like signature marked by high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis.

SIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice.

Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions.

SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice.

Sirtuins (SIRT1-7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice.

Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling.

Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes.

SIRT7 Deficiency Protects against Aβ-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by irreversible memory loss and cognitive decline. The deposition of amyloid-β (Aβ), especially aggregation-prone Aβ, is considered to be an early event preceding neurodegeneration in AD. Sirtuins (SIRT1-7 in mammals) are nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases, and several sirtuins play important roles in AD.

NAD + salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity.

Background And Aims: Natural killer (NK) cells are key players in tumor immunosurveillance, and metabolic adaptation manipulates their fate and functional state. The nicotinamide adenine dinucleotide (NAD + ) has emerged as a vital factor to link cellular metabolism and signaling transduction. Here, we identified NAD + metabolism as a central hub to determine the homeostasis and function of NK cells.

Development of a DELFIA method to detect oncofetal antigen ROR1-positive exosomes.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed in a wide variety of hematological and solid cancers, but is low or absent in adult tissues. Here, we show that ROR1 is released with exosomes from ROR1-positive cancer cells. We also developed a simple dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) to detect cancer-derived ROR1-positive exosomes, which are captured by two anti-ROR1 antibodies and detected by the fluorescence of free chelating europium.

SIRT7 regulates lipogenesis in adipocytes through deacetylation of PPARγ2.

Aims/introduction: Peroxisome proliferator-activated receptor (PPAR)-γ2 is a transcription factor crucial for regulating adipogenesis and glucose/lipid metabolism, and synthetic PPARγ ligands, such as thiazolidinediones, are effective oral medication for type 2 diabetes. Sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide-dependent deacetylase, also controls metabolism. However, it is not known whether SIRT7 regulates the function of PPARγ2 by its deacetylation.

Sirt7 Deficiency Attenuates Neointimal Formation Following Vascular Injury by Modulating Vascular Smooth Muscle Cell Proliferation.

Background: Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.

Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation.

Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear.

Impact of tissue macrophage proliferation on peripheral and systemic insulin resistance in obese mice with diabetes.

Introduction: Obesity-related insulin resistance is a widely accepted pathophysiological feature in type 2 diabetes. Systemic metabolism and immunity are closely related, and obesity represents impaired immune function that predisposes individuals to systemic chronic inflammation. Increased macrophage infiltration and activation in peripheral insulin target tissues in obese subjects are strongly related to insulin resistance.

HNF1α controls glucagon secretion in pancreatic α-cells through modulation of SGLT1.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor required for normal insulin secretion and maintenance of β-cell number in the pancreas. HNF1α is also expressed in pancreatic α-cells, but its role in these cells is unknown. The aim of this study was to clarify the role of HNF1α in α-cells.

Brown adipocyte-derived exosomal miR-132-3p suppress hepatic Srebf1 expression and thereby attenuate expression of lipogenic genes.

Recent evidence has revealed a novel signaling mechanism through which brown adipose tissue (BAT)-derived exosomal microRNAs (miRNAs) influence hepatic gene expression. Here, we uncover neuronal control of these miRNAs and identify exosomal miR-132-3p as a regulator of hepatic lipogenesis under cold stress conditions. Norepinephrine, a sympathetic nervous system neurotransmitter mediating cold-induced BAT activation, altered the composition of brown adipocyte (BAC)-derived exosomal miRNAs; among them, miR-132-3p was significantly induced.

Cardiomyocyte Sirt (Sirtuin) 7 Ameliorates Stress-Induced Cardiac Hypertrophy by Interacting With and Deacetylating GATA4.

Sirt (Sirtuin) 7, the most recently identified mammalian sirtuin, has been shown to contribute to appropriate wound healing processes after acute cardiovascular insult. However, its role in the development of cardiac remodeling after pressure overload is unclear. Cardiomyocyte-specific Sirt7-knockout and control mice were subjected to pressure overload induced by transverse aortic constriction.

SIRT7 regulates the nuclear export of NF-κB p65 by deacetylating Ran.

Sirtuin 7 (SIRT7) is an NAD-dependent lysine deacetylase that regulates diverse biological processes. We recently observed that SIRT7 deficiency suppresses the nuclear accumulation of p65, which is a component of nuclear factor kappa B. However, the underlying molecular mechanism remains elusive.

SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix.

SP7/Osterix (OSX) is a master regulatory transcription factor that activates a variety of genes during differentiation of osteoblasts. However, the influence of post-translational modifications on the regulation of its transactivation activity is largely unknown. Here, we report that sirtuins, which are NAD(+)-dependent deacylases, regulate lysine deacylation-mediated transactivation of OSX.

Sirtuin 7 Deficiency Ameliorates Cisplatin-induced Acute Kidney Injury Through Regulation of the Inflammatory Response.

Cisplatin-induced acute kidney injury (AKI) has been recognized as one of cisplatin's serious side effects, limiting its use in cancer therapy. Sirtuin 1 (SIRT1) and SIRT3 play protective roles against cisplatin-induced kidney injury. However, the role of SIRT7 in cisplatin-induced kidney injury is not yet known.

Inhibition of Local Macrophage Growth Ameliorates Focal Inflammation and Suppresses Atherosclerosis.

Objective: Macrophages play a central role in various stages of atherosclerotic plaque formation and progression. The local macrophages reportedly proliferate during atherosclerosis, but the pathophysiological significance of macrophage proliferation in this context remains unclear. Here, we investigated the involvement of local macrophage proliferation during atherosclerosis formation and progression using transgenic mice, in which macrophage proliferation was specifically suppressed.

SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development.

Sirtuins (SIRT1-7) are NAD-dependent deacetylase/deacylases that regulate a wide variety of biological functions. Although the roles of sirtuins in cartilage homeostasis and cartilage diseases have been well studied, there is no information on the contribution of SIRT7 to cartilage homeostasis and osteoarthritis (OA) pathologies. Here, we demonstrate that Sirt7 knockout mice are resistant to the development of aging-associated OA and forced exercise-induced OA.

Transcriptional Regulation of Metabolism by SIRT1 and SIRT7.

Sirtuins are a family of evolutionally conserved nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases/deacylases that regulate metabolism. The mammalian sirtuin family consists of seven sirtuins (SIRT1-7). Recent findings have identified critical roles for SIRT1 and SIRT7 in glucose/lipid metabolism in multiple tissues.

Age-dependent increase in angiopoietin-like protein 2 accelerates skeletal muscle loss in mice.

Skeletal muscle atrophy, or sarcopenia, is commonly observed in older individuals and in those with chronic disease and is associated with decreased quality of life. There is recent medical and broad concern that sarcopenia is rapidly increasing worldwide as populations age. At present, strength training is the only effective intervention for preventing sarcopenia development, but it is not known how this exercise regimen counteracts this condition.

Sirtuin 7 is involved in the consolidation of fear memory in mice.

Sirtuin 7 (SIRT7) is an NAD-dependent deacetylase/deacylase, and is involved in a variety of biological processes relevant to the transcription of rRNA, the DNA damage response, tumorigenesis, and metabolism. SIRT7 mRNA is expressed ubiquitously, including in the brain, but there is no detailed information about the anatomical distribution and functional role of SIRT7 in the brain. Here, we demonstrated that SIRT7 is widely expressed in the mouse brain, including in the cortex, striatum, thalamus, hippocampus, and amygdala.