Autophagy and Cardiometabolic Diseases

From Molecular Mechanisms to Translational Medicine

Jun Ren, James R. Sowers, Yingmei Zhang

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128054420
• Topic: Medicine
• Subtopic: Cardiology

Autophagy and Cardiometabolic Diseases: From Moleculer Mechanisms to Translational Medicine covers the science of autophagy in relation to cardiometabolic diseases and the future therapeutic potentials of autophagy regulation in these processes. Processes are not described in isolation, but in concert with other cellular and/or metabolic processes, such as lipogenesis, glucose, energy metabolism and apoptosis. This approach recognizes the multifactorial nature of cardiometabolic diseases, including obesity, diabetes, insulin resistance, hypertension and dyslipidemia. The book provides explanations, while also distinguishing the delicate role for autophagy in pathogenesis and exploring complications for cardiometabolic diseases.

By targeting autophagy, it offers new avenues for drug discovery and treatment for cardiometabolic anomalies. It is a perfect resource for cardiology researchers, scientists and medical practitioners.

• Explains the processes inherent in the protein quality control for pathogenesis and complications of cardiometabolic diseases
• Provides knowledge from internationally recognized contributors in the field
• Incorporates a translational approach, covering the basic cellular biology of autophagy and presenting the role of autophagy regulation for both pathogenesis and complication in cardiometabolic diseases
• Contains access to a companion website with additional illustrations

Section II

Autophagy and Pathogenesis of Cardiometabolic Disease

Chapter 7

Autophagy and Diabetes Mellitus

Yingmei Zhang⁎^{,† ⁎} Zhongshan Hospital Fudan University, Shanghai, China
^† University of Wyoming College of Health Sciences, Laramie, WY, United States

Abstract

Autophagy is an evolutionally conserved homeostatic process involving consecutive cellular steps for degrading and recycling aged or injured cytoplasmic components. Ample studies have indicated that a key role for basal autophagy in the maintenance of cellular homeostasis and function. However, inadequate or excessive autophagy in pathological conditions results may contribute to the impaired organismal function including development of diabetes and diabetic complications. Diabetes mellitus is a serious multifactorial metabolic disease linked to the high risk of cardiovascular and other chronic noncommunicable diseases. Increased lipotoxicity, inflammation, and oxidative stress are considered to contribute to the metabolic abnormalities in diabetic complications. Recent findings have also suggested a pivotal role for dysregulated autophagy in diabetogenesis and diabetic organ complications. Nonetheless, molecular mechanisms of dysregulated autophagy in diabetes are rather complex and involve multiple signaling pathways cooperating at various levels. This chapter summarizes recent advances in the molecular mechanisms behind autophagic regulation in diabetes and diabetic complications. A thorough and in-depth understanding on the molecular mechanisms leading to autophagy dysregulation in diabetes should offer promises toward new therapies for diabetes and diabetic complications.

Keywords

Autophagy; Diabetes mellitus; Mitochondria

Acknowledgment

This work in author's laboratory has been supported in part by Grants from Natural Science Foundation of China (81522004 and 81370195).

7.1 Introduction

Autophagy denotes a conserved cellular process to recycle aged or injured organelles in an effort to preserve energy, and remove senescent or damaged proteins/organelles [1,2]. It is well perceived that basal autophagy serves as a housekeeper in physiological condition through degrading intracellular aged or damaged proteins and organelles [2–5]. Thus autophagy may work through a cell-protective mechanism against stress and may serve as a cellular program in response to the daily wear and tear [6]. Paradoxically, maladaptive or excessive autophagy also leads to a type of nonapoptotic cell death, namely, type 2 programmed or autophagic cell death [6,7]. Autophagy may be induced by intracellular or extracellular stress to exert a broad range of physiological and pathophysiological responses. It has been shown that autophagy exerts either protective or destructive role, depending on the nature of pathological stress. It is believed that autophagy is essential for cell survival, sustained activation of which induces autophagic or apoptotic cell death [1,6,8]. Dysregulated autophagy is noted in a variety of cardiac anomalies including cardiac hypertrophy under pressure overload [9,10]. Cardiac remodeling is also commonly seen in diabetic heart complications [11]. Although diabetes is known to trigger dysregulation of autophagic response in a variety of organs including pancreas [12], the impact of diabetes and hyperglycemia on autophagy in the heart has not been examined until recently [13–15]. Here we will compare the autophagic responses in both types of diabetes and discuss molecular signaling mechanisms behind the regulation of autophagy in diabetes.

Diabetes mellitus is a series of devastating chronic metabolic disorders involving carbohydrate, lipid, and protein metabolism [16,17]. It is estimated that diabetes constitutes the 7th leading cause of death by 2030 according to the World Health Organization [18]. Diabetes mellitus induces a wide array of end-organ complications including diabetic nephropathy, retinopathy, and peripheral vasculopathy, due to diabetes-associated risk factors including obesity, hypercholesterolemia, atherosclerosis, and hypertension [11,19,20]. Numerous epidemiological and experimental studies have indicated a role for diabetes as a major independent risk factor for cardiac diseases, namely, diabetic cardiomyopathy independent of any macro- or microvascular diseases [17,19].

7.2 Autophagy and the Diabetes Mellitus Pathogenic Process

Diabetes is featured by hyperglycemia due to insufficient insulin secretion or sensitivity, or both. In type 1 diabetes mellitus (T1D), abnormal hyperglycemia arises from a lack of insulin production, while insulin resistance is mainly responsible for elevated blood glucose levels in type 2 diabetes mellitus (T2D) [21,22]. In both situations, persistent hyperglycemia leads to an imbalance between prooxidant and antioxidant capacity, resulting in oxidative/nitrosative stress. This type of pathophysiological phenomenon serves as a common denominator for both types of diabetes. Impaired autophagy has been reported in diabetes and diabetes organ complications [15,23]. Defective autophagy results in the accumulation of dysfunctional organelles such as mitochondria in diabetes. Mitochondria are both the production site and target of reactive oxygen species (ROS). It is perceived that imbalance between ROS toxicity and autophagy cytoprotection prompts to further ROS accumulation and compromised mitochondrial function, leading to compromised insulin sensitivity [24,25]. Therefore damaged mitochondria and ROS production may form a vicious cycle for organ damage. Not surprisingly, increased ROS production and mitochondrial injury are commonly seen in the hearts from both types of diabetes in patients and experimental animals [26]. Although a causative role for ROS was noted for diabetic complications by the reversal of diabetic organ injury using antioxidants [27], such success in experimental antioxidant therapy has not been successfully reproduced in diabetic patients, suggesting that simply retarding existing ROS using antioxidants is inadequate to reduce organ injury in diabetes. Thus it is pertinent to develop better and more effective therapeutic strategies against diabetic complications to remove aged or defective mitochondria which would otherwise produce ROS or other proapoptotic mediators. Autophagy, in particular, mitochondria-selective autophagy “mitophagy” seems to be the right player to improve the efficiency of mitochondria. In addition to garbage clearance, defective autophagy also prompts to diabetogenesis through onset of compromised insulin sensitivity. It has been demonstrated that autophagy directly controls insulin responsiveness in various tissues such as adipose tissues, skeletal muscles, liver, brain, and pancreas [28–30]. When the ability of adipose tissue to store surplus energy is exceeded, lipids accumulate ectopically in the liver and muscle prompting insulin resistance and impaired pancreatic function.

7.2.1 Hepatic Autophagy in Diabetes

The liver serves as the target for metabolic diseases and is central to the control of energy homeostasis. Autophagy contributes to the replenishment of amino acid pool necessary for hepatic gluconeogenesis and ATP production via tricarboxylic acid cycle [8]. Autophagy also plays a key role in hepatic homeostasis through lipophagy, that is, degradation of liver lipid droplets, to produce free fatty acids. Aberrant regulation of hepatic autophagy is common in metabolic diseases such as obesity, diabetes, and fatty liver diseases. For example, dampened hepatic autophagy is found in both genetic and diet-induced obesity [31,32]. Overtly increased hepatic lipid levels were found in mice with hepatocyte-specific Atg7 knockout. Suppression of Atg7 in vitro and in vivo prompted insulin resistance whereas reconstitution of Atg7 or autophagy alleviated obesity-associated anomalies in ER stress, glucose intolerance, and insulin resistance [31]. These pieces of evidence supported the notion that dysregulated autophagy is causal to dampened hepatic insulin sensitivity and glucose homeostasis [32]. ER function, mainly presented in the form of unfolded protein response, is another key factor for obesogenesis and diabetogenesis. Recent evidence suggested that autophagy may help to degrade and clear misfolded proteins from β cell cytoplasm. Somewhat to our surprise, targeted disruption of Atg7 in mouse livers exhibited low body weight and fat content along with improved glucose tolerance under normal or high-fat diet intake [33], suggesting possible dual regulation of autophagy by Atg7 on hepatic lipid metabolism. Although these pieces of evidence favored an essential role for autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), modulation of autophagy for the treatment of NAFLD may require a more targeted approach given the presence of enhanced macroautophagy in hepatic stellate cells in the face of hepatic fibrosis. In addition to classical autophagy pathway, FNDC5 deficiency was shown...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Foreword
• Acknowledgments
• Introduction
• Section I: Cell Biology of Cardiometabolic Syndrome and Autophagy
• Section II: Autophagy and Pathogenesis of Cardiometabolic Disease
• Section III: Autophagy and Complications of Cardiometabolic Disease
• Section IV: Translational Approach of Autophagy
• Index