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Molecular Aspects of Medicine Dec 2021The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and... (Review)
Review
The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and bile acid synthesis as well as drug/xenobiotic metabolism and detoxification. Research from the past decades indicate that autophagy, the cellular catabolic process mediated by lysosomes, plays an important role in maintaining cellular and metabolic homeostasis in the liver. Hepatic autophagy fluctuates with hormonal cues and the availability of nutrients that respond to fed and fasting states as well as circadian activities. Dysfunction of autophagy in liver parenchymal and non-parenchymal cells can lead to various liver diseases including non-alcoholic fatty liver diseases, alcohol associated liver disease, drug-induced liver injury, cholestasis, viral hepatitis and hepatocellular carcinoma. Therefore, targeting autophagy may be a potential strategy for treating these various liver diseases. In this review, we will discuss the current progress on the understanding of autophagy in liver physiology. We will also discuss several forms of selective autophagy in the liver and the molecular signaling pathways in regulating autophagy of different cell types and their implications in various liver diseases.
Topics: Autophagy; Humans; Lipid Metabolism; Liver; Liver Neoplasms; Non-alcoholic Fatty Liver Disease
PubMed: 34120768
DOI: 10.1016/j.mam.2021.100973 -
Developmental Cell Apr 2021Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression;... (Review)
Review
Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Macroautophagy; Mitophagy; Neoplasms
PubMed: 33689692
DOI: 10.1016/j.devcel.2021.02.010 -
Nature Reviews. Molecular Cell Biology Mar 2023'Autophagy' refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes... (Review)
Review
'Autophagy' refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes for degradation. Different forms of autophagy have been described on the basis of the nature of the cargoes and the means used to deliver them to lysosomes. At present, the prevailing categories of autophagy in mammalian cells are macroautophagy, microautophagy and chaperone-mediated autophagy. The molecular mechanisms and biological functions of macroautophagy and chaperone-mediated autophagy have been extensively studied, but microautophagy has received much less attention. In recent years, there has been a growth in research on microautophagy, first in yeast and then in mammalian cells. Here we review this form of autophagy, focusing on selective forms of microautophagy. We also discuss the upstream regulatory mechanisms, the crosstalk between macroautophagy and microautophagy, and the functional implications of microautophagy in diseases such as cancer and neurodegenerative disorders in humans. Future research into microautophagy will provide opportunities to develop novel interventional strategies for autophagy- and lysosome-related diseases.
Topics: Animals; Humans; Microautophagy; Autophagy; Lysosomes; Cell Communication; Macroautophagy; Mammals
PubMed: 36097284
DOI: 10.1038/s41580-022-00529-z -
Cell Death & Disease Oct 2023Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role... (Review)
Review
Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors.
Topics: Endoplasmic Reticulum Stress; Autophagy; Endoplasmic Reticulum; Mitophagy; Cell Death
PubMed: 37794028
DOI: 10.1038/s41419-023-06154-8 -
EMBO Reports Aug 2022Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to... (Review)
Review
Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to this organelle control by degrading the excess or defective portions of organelles. The endoplasmic reticulum (ER) is an organelle with distinct structural domains associated with specific functions. The ER dynamically changes its mass, components, and shape in response to metabolic, developmental, or proteotoxic cues to maintain or regulate its functions. Therefore, elaborate mechanisms are required for proper degradation of the ER. Here, we review our current knowledge on diverse mechanisms underlying selective autophagy of the ER, which enable efficient degradation of specific ER subdomains according to different demands of cells.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Macroautophagy
PubMed: 35758175
DOI: 10.15252/embr.202255192 -
Annual Review of Nutrition 2015Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy.... (Review)
Review
Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene Atg7 increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.
Topics: Animals; Autophagy; Autophagy-Related Protein 7; Gene Deletion; Hepatocytes; Homeostasis; Humans; Lipase; Lipid Droplets; Lipid Metabolism; Liver; Liver Diseases; Non-alcoholic Fatty Liver Disease; Signal Transduction; Ubiquitin-Activating Enzymes
PubMed: 26076903
DOI: 10.1146/annurev-nutr-071813-105336 -
Frontiers in Endocrinology 2020Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.
Topics: Animals; Autophagy; Homeostasis; Humans; Lipogenesis; Non-alcoholic Fatty Liver Disease
PubMed: 33597924
DOI: 10.3389/fendo.2020.601627 -
International Journal of Molecular... Nov 2023Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid droplets, along with their protein composition, mainly including perilipins, have been implicated in the etiology of the disease. These proteins have garnered increasing attention as a pivotal regulator since their levels and distinct expression appear to be associated with the progression from simple steatosis to steatohepatitis. Perilipins are target proteins of chaperone-mediated autophagy, and their degradation is a prerequisite for lipolysis and lipophagy to access the lipid core. Both lipophagy and chaperone-mediated autophagy have significant implications on the development of the disease, as evidenced by their upregulation during the initial phases of simple steatosis and their subsequent downregulation once steatosis is established. On the contrary, during steatohepatitis, the process of chaperone-mediated autophagy is enhanced, although lipophagy remains suppressed. Evidently, the reduced levels of autophagic pathways observed in simple steatosis serve as a defensive mechanism against lipotoxicity. Conversely, in steatohepatitis, chaperone-mediated autophagy fails to compensate for the continuous generation of small lipid droplets and thus cannot protect hepatocytes from lipotoxicity.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Chaperone-Mediated Autophagy; Lipid Droplets; Lipid Metabolism; Hepatocytes; Autophagy; Perilipins; Liver
PubMed: 37958873
DOI: 10.3390/ijms242115891 -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2022Lipophagy is a kind of selective autophagy, which can selectively identify and degrade lipid droplets and plays an important role in regulating cellular lipid metabolism... (Review)
Review
Lipophagy is a kind of selective autophagy, which can selectively identify and degrade lipid droplets and plays an important role in regulating cellular lipid metabolism and maintaining intracellular lipid homeostasis. Exercise can induce lipophagy and it is also an effective means of reducing body fat. In this review, we summarized the relationship between exercise and lipophagy in the liver, pancreas, adipose tissue, and the possible molecular mechanisms to provide a new clue for the prevention and treatment of fatty liver, obesity and other related metabolic diseases by exercise.
Topics: Autophagy; Humans; Lipid Droplets; Lipid Metabolism; Liver; Metabolic Diseases
PubMed: 35503079
DOI: No ID Found -
Bone Feb 2023The mechanism of the impact of hyperlipidemia on bone tissue homeostasis is unclear, and the role of lipophagy is yet to be investigated. This study investigated changes...
The mechanism of the impact of hyperlipidemia on bone tissue homeostasis is unclear, and the role of lipophagy is yet to be investigated. This study investigated changes in lipophagy and osteogenesis levels under hyperlipemic conditions and explored the effects of lipophagy on bone regeneration. In vivo, femurs of mice with diet-induced moderate hyperlipidemia were ground out with a ball drill to create defects. In vitro, mouse osteoblast cell lines were grown in two different concentrations of the high-fat medium. We found that at hyperphysiological of lipid conditions, activation of lipophagy restored osteoblast function in a way, and similar results were observed in mice with diet-induced hyperlipidemia. Still, at suprahyperphysiological concentrations of lipid culture, the activation of lipophagy further inhibited osteogenesis, and inhibition of autophagy instead promoted osteogenesis to a small extent. These results demonstrate that lipophagy functions differently in diverse high-fat environments, suggesting that cellular and organismal changes in response to high-fat stimuli are dynamic. This may provide new ideas for improving bone dysfunction caused by lipid metabolism disorders.
Topics: Animals; Mice; Lipid Metabolism; Hyperlipidemias; Osteogenesis; Autophagy; Lipids
PubMed: 36513279
DOI: 10.1016/j.bone.2022.116643