Mol. Cells 2018; 41(1): 11-17
Published online January 23, 2018
https://doi.org/10.14348/molcells.2018.2228
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: mslee0923@yuhs.ac
Autophagy is critical for the maintenance of organelle function and intracellular nutrient environment. Autophagy is also involved in systemic metabolic homeostasis, and its dysregulation can lead to or accelerate the development of metabolic disorders. While the role of autophagy in the global metabolism of model organisms has been investigated mostly using site-specific genetic knockout technology, the impact of dysregulated autophagy on systemic metabolism has been unclear. Here, we review recent papers showing the role of autophagy in systemic metabolism and in the development of metabolic disorders. Also included are data suggesting the role of autophagy in human-type diabetes, which are different in several key aspects from murine models of diabetes. The results shown here support the view that autophagy modulation could be a new modality for the treatment of metabolic syndrome associated with lipid overload and human-type diabetes.
Keywords amyloid, autophagy, diabetes, inflammasome, metabolism
Autophagy, literally meaning ‘self-eating,’ is a cellular process of degradation of the cell’s own internal material, such as proteins or organelles, in lysosomes. There are three major types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Among them, macroautophagy (hereafter referred to as autophagy) is a process involving the rearrangement of subcellular membranes, sequestering the cytoplasm and organelles, which leads to the formation of an autophagosome surrounded by a double membrane. When autophagosomes fuse with lysosomes, autophagolysosomes are formed in which proteolysis of the sequestered material by lysosomal enzymes occurs (Klionsky and Emr, 2000). The main purpose of autophagy is quality control of organelles or proteins, and protection of the intra-cellular nutrient environment. Thus, in the case of nutrient deficiency, intracellular macromolecules are degraded by autophagy to meet cellular requirements for energy and vital elements, suggesting that adaptive autophagy may have evolved from ancient cellular machinery supplying nutrients during energy crises in primordial unicellular organisms such as yeast. The autophagy machinery has been extensively characterized by many scientists, and the 2016 Nobel Prize for Physiology or Medicine was awarded to Yoshinori Ohsumi as a tribute to his seminal discovery of the autophagy-related (Atg) conjugation system. Outlining the detailed molecular and cellular mechanisms of autophagy is beyond the scope of this paper, and the readers are encouraged to consult excellent, previously published reviews (Klionsky, 2016; Mizushima and Komatsu, 2011).
Since autophagy is critical for the maintenance of cellular homeostasis and organelle function, it affects almost all physiological processes and, furthermore, is expected to influence the pathogenesis of a diverse range of diseases. Thus, dysregulated autophagy may lead to or be associated with a variety of diseases, including metabolic disorders such as type 2 diabetes (T2D) or metabolic syndrome, neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease, immune/inflammatory disorders, infectious diseases, cancer and aging. Accordingly, autophagy modulation may have therapeutic potential on such disorders and conditions (Eisenberg et al., 2009; Rubinsztein et al., 2012; Shoji-Kawata et al., 2013; Zhang et al., 2007).
In this review, we summarize the recent progress made in understanding the role of systemic and local autophagy in the pathogenesis of metabolic disorders, and the prospect of using autophagy modulators as a new therapeutic option against diabetes and metabolic disorders.
Two main pathogenic axes in the development of T2D are insulin resistance and β-cell failure. Numerous theories have been proposed as mechanisms causing insulin resistance and β-cell failure such as lipid overload, reactive oxygen species, ER stress, mitochondrial dysfunction and low-grade metabolic inflammation (Johnson and Olefsky, 2013). Besides such well-recognized factors, dysregulated autophagy and altered gut microbiota have recently been implicated as contributing factors (Kim and Lee, 2014; Yang et al., 2017). While extensively studied, the role of autophagy in the maintenance of metabolic homeostasis and in the pathogenesis of metabolic disorders has been controversial, which is partly due to the neonatal lethality of mice with systemic autophagy-knockout. Thus, the
Such diverse metabolic features of mice with autophagy knockout in various metabolic tissues raise a question – what is the effect of global autophagy insufficiency of a physiological level on systemic metabolism and the development of metabolic disorders, since there is neither ‘tissue-specific’ autophagy nor ‘gene knockout’ in the real world. To answer this question, mice with systemic autophagy insufficiency of a physiologically relevant degree have been generated (Lim et al., 2014). Such
Thus, increased inflammasome activation due to inefficient clearance of dysfunctional mitochondria acting as a hub for inflammasome activation (Misawa et al., 2013) and increased lipid content probably due to compromised lipophagy are the main culprits leading to the aggravated metabolic deterioration seen in
So far, we have discussed the role of autophagy in diabetes based on data generated using animal models. However, human diabetes and murine diabetes differ in several aspects. One of the key differences is the accumulation of amyloids in islets that occurs in human diabetes but not in murine diabetes. Islet amyloid stained with Congo red is found in 90% of human subjects with diabetes (Kahn et al., 1999). This striking dissimilarity is due to the differences in the amino acid sequence of islet amyloid polypeptide (IAPP) between mice and humans. Human IAPP (hIAPP) is amyloidogenic, and murine IAPP (mIAPP) is nonamyloidogenic (Westermark et al., 2011), although it remains unclear why humans acquired IAPP amyloidogenicity during evolution. Amyloidogenic or aggregate-prone proteins are preferentially cleared by autophagy, while nonamyloidogenic or soluble proteins can be cleared by both autophagy and proteasome pathways (Rubinsztein, 2006). Thus, the role of autophagy in human diabetes would be greater than in murine diabetes. To study the role of autophagy in human-type diabetes, transgenic mice expressing hIAPP in pancreatic β-cells driven by the rat insulin promoter (
When the mechanism of overt diabetes in
Since autophagy deficiency can lead to hIAPP oligomer formation, β-cell apoptosis and, finally, diabetes, the possibility that autophagy enhancement could improve β-cell function by accelerating clearance of hIAPP oligomers has been tested. To this end,
While these results show that enhancement of β-cell autophagy leads to improvement of β-cell function by clearing hIAPP oligomer, a recent paper suggested a different role of starvation-induced autophagy of pancreatic β-cells such as degradation of insulin granules inhibiting excessive release of insulin during fasting (Goginashvili et al., 2015). Thus, further studies will be required to unravel the functional complexity regarding the role of β-cell autophagy in the physiological condition and in the pathological context.
A number of mouse studies employing tissue-specific knockout of essential autophagy genes have revealed the important role and function of autophagy in controlling metabolic function. However, it has not been clear from those genetic studies how dysregulated autophagy could affect global or systemic metabolic features. Considering recent evidence that autophagy and mitophagy declines in aging (Sun et al., 2015), such a question could be a practical one related to the effect of aging and organelle dysfunction on body metabolism. Now, it is considered very likely that autophagy deficiency due to aging, genetic causes, or other factors could compromise an organism’s ability to adapt to metabolic stress, and predispose it to the development of metabolic syndrome and diabetes due to increased lipid accumulation and inflammasome activation when confronted by metabolic or other types of stress (Fig. 3). Autophagy deficiency could be a predisposing factor for human-type diabetes in particular, since hIAPP oligomers or amyloids are preferentially cleared by autophagy (Fig. 3). Thus, it is highly likely that enhancement of autophagy could be a novel strategy against a global increase in the incidence of metabolic syndrome and diabetes.
Mol. Cells 2018; 41(1): 11-17
Published online January 31, 2018 https://doi.org/10.14348/molcells.2018.2228
Copyright © The Korean Society for Molecular and Cellular Biology.
Jinyoung Kim, Yu-Mi Lim, and Myung-Shik Lee*
Severance Biomedical Science Institute & Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
Correspondence to:*Correspondence: mslee0923@yuhs.ac
Autophagy is critical for the maintenance of organelle function and intracellular nutrient environment. Autophagy is also involved in systemic metabolic homeostasis, and its dysregulation can lead to or accelerate the development of metabolic disorders. While the role of autophagy in the global metabolism of model organisms has been investigated mostly using site-specific genetic knockout technology, the impact of dysregulated autophagy on systemic metabolism has been unclear. Here, we review recent papers showing the role of autophagy in systemic metabolism and in the development of metabolic disorders. Also included are data suggesting the role of autophagy in human-type diabetes, which are different in several key aspects from murine models of diabetes. The results shown here support the view that autophagy modulation could be a new modality for the treatment of metabolic syndrome associated with lipid overload and human-type diabetes.
Keywords: amyloid, autophagy, diabetes, inflammasome, metabolism
Autophagy, literally meaning ‘self-eating,’ is a cellular process of degradation of the cell’s own internal material, such as proteins or organelles, in lysosomes. There are three major types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Among them, macroautophagy (hereafter referred to as autophagy) is a process involving the rearrangement of subcellular membranes, sequestering the cytoplasm and organelles, which leads to the formation of an autophagosome surrounded by a double membrane. When autophagosomes fuse with lysosomes, autophagolysosomes are formed in which proteolysis of the sequestered material by lysosomal enzymes occurs (Klionsky and Emr, 2000). The main purpose of autophagy is quality control of organelles or proteins, and protection of the intra-cellular nutrient environment. Thus, in the case of nutrient deficiency, intracellular macromolecules are degraded by autophagy to meet cellular requirements for energy and vital elements, suggesting that adaptive autophagy may have evolved from ancient cellular machinery supplying nutrients during energy crises in primordial unicellular organisms such as yeast. The autophagy machinery has been extensively characterized by many scientists, and the 2016 Nobel Prize for Physiology or Medicine was awarded to Yoshinori Ohsumi as a tribute to his seminal discovery of the autophagy-related (Atg) conjugation system. Outlining the detailed molecular and cellular mechanisms of autophagy is beyond the scope of this paper, and the readers are encouraged to consult excellent, previously published reviews (Klionsky, 2016; Mizushima and Komatsu, 2011).
Since autophagy is critical for the maintenance of cellular homeostasis and organelle function, it affects almost all physiological processes and, furthermore, is expected to influence the pathogenesis of a diverse range of diseases. Thus, dysregulated autophagy may lead to or be associated with a variety of diseases, including metabolic disorders such as type 2 diabetes (T2D) or metabolic syndrome, neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease, immune/inflammatory disorders, infectious diseases, cancer and aging. Accordingly, autophagy modulation may have therapeutic potential on such disorders and conditions (Eisenberg et al., 2009; Rubinsztein et al., 2012; Shoji-Kawata et al., 2013; Zhang et al., 2007).
In this review, we summarize the recent progress made in understanding the role of systemic and local autophagy in the pathogenesis of metabolic disorders, and the prospect of using autophagy modulators as a new therapeutic option against diabetes and metabolic disorders.
Two main pathogenic axes in the development of T2D are insulin resistance and β-cell failure. Numerous theories have been proposed as mechanisms causing insulin resistance and β-cell failure such as lipid overload, reactive oxygen species, ER stress, mitochondrial dysfunction and low-grade metabolic inflammation (Johnson and Olefsky, 2013). Besides such well-recognized factors, dysregulated autophagy and altered gut microbiota have recently been implicated as contributing factors (Kim and Lee, 2014; Yang et al., 2017). While extensively studied, the role of autophagy in the maintenance of metabolic homeostasis and in the pathogenesis of metabolic disorders has been controversial, which is partly due to the neonatal lethality of mice with systemic autophagy-knockout. Thus, the
Such diverse metabolic features of mice with autophagy knockout in various metabolic tissues raise a question – what is the effect of global autophagy insufficiency of a physiological level on systemic metabolism and the development of metabolic disorders, since there is neither ‘tissue-specific’ autophagy nor ‘gene knockout’ in the real world. To answer this question, mice with systemic autophagy insufficiency of a physiologically relevant degree have been generated (Lim et al., 2014). Such
Thus, increased inflammasome activation due to inefficient clearance of dysfunctional mitochondria acting as a hub for inflammasome activation (Misawa et al., 2013) and increased lipid content probably due to compromised lipophagy are the main culprits leading to the aggravated metabolic deterioration seen in
So far, we have discussed the role of autophagy in diabetes based on data generated using animal models. However, human diabetes and murine diabetes differ in several aspects. One of the key differences is the accumulation of amyloids in islets that occurs in human diabetes but not in murine diabetes. Islet amyloid stained with Congo red is found in 90% of human subjects with diabetes (Kahn et al., 1999). This striking dissimilarity is due to the differences in the amino acid sequence of islet amyloid polypeptide (IAPP) between mice and humans. Human IAPP (hIAPP) is amyloidogenic, and murine IAPP (mIAPP) is nonamyloidogenic (Westermark et al., 2011), although it remains unclear why humans acquired IAPP amyloidogenicity during evolution. Amyloidogenic or aggregate-prone proteins are preferentially cleared by autophagy, while nonamyloidogenic or soluble proteins can be cleared by both autophagy and proteasome pathways (Rubinsztein, 2006). Thus, the role of autophagy in human diabetes would be greater than in murine diabetes. To study the role of autophagy in human-type diabetes, transgenic mice expressing hIAPP in pancreatic β-cells driven by the rat insulin promoter (
When the mechanism of overt diabetes in
Since autophagy deficiency can lead to hIAPP oligomer formation, β-cell apoptosis and, finally, diabetes, the possibility that autophagy enhancement could improve β-cell function by accelerating clearance of hIAPP oligomers has been tested. To this end,
While these results show that enhancement of β-cell autophagy leads to improvement of β-cell function by clearing hIAPP oligomer, a recent paper suggested a different role of starvation-induced autophagy of pancreatic β-cells such as degradation of insulin granules inhibiting excessive release of insulin during fasting (Goginashvili et al., 2015). Thus, further studies will be required to unravel the functional complexity regarding the role of β-cell autophagy in the physiological condition and in the pathological context.
A number of mouse studies employing tissue-specific knockout of essential autophagy genes have revealed the important role and function of autophagy in controlling metabolic function. However, it has not been clear from those genetic studies how dysregulated autophagy could affect global or systemic metabolic features. Considering recent evidence that autophagy and mitophagy declines in aging (Sun et al., 2015), such a question could be a practical one related to the effect of aging and organelle dysfunction on body metabolism. Now, it is considered very likely that autophagy deficiency due to aging, genetic causes, or other factors could compromise an organism’s ability to adapt to metabolic stress, and predispose it to the development of metabolic syndrome and diabetes due to increased lipid accumulation and inflammasome activation when confronted by metabolic or other types of stress (Fig. 3). Autophagy deficiency could be a predisposing factor for human-type diabetes in particular, since hIAPP oligomers or amyloids are preferentially cleared by autophagy (Fig. 3). Thus, it is highly likely that enhancement of autophagy could be a novel strategy against a global increase in the incidence of metabolic syndrome and diabetes.
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