Chinese Journal of Physiology

REVIEW ARTICLE
Year : 2019  |  Volume : 62  |  Issue : 2  |  Page : 53--62

Autophagy: A potential target for rescuing sepsis-induced hepatic failure

Chin Hsu 
 Department of Physiology, Faculty of Medicine, College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence Address:
Prof. Chin Hsu
Department of Physiology, Faculty of Medicine, College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung
Taiwan

Abstract

Sepsis is the leading cause of death in intensive care units worldwide; however, it remains a scientific and clinical challenge in modern medicine. An excessive inflammatory response associated with high level of reactive oxygen species results in mitochondrial dysfunction and activation of the unfolded protein response leading to subsequent energetic organ failure in septic patients. In addition to blocking the inflammatory cascade directly, new strategies focusing on host endogenous adaption to severe infection may hold better promise for improving outcomes in septic patients. Autophagy is a fundamental cellular response to stress and pathogen invasion. The study of autophagic responses to sepsis is a critical component of understanding the mechanisms by which tissues respond to infection. This review aims at elucidating the role of autophagy in sepsis-induced hepatic failure and further explores the possible factor that suppresses autophagy and potential targets of augmenting autophagy, in an effort to provide a new perspective for the clinical treatment of sepsis-induced hepatic failure.


How to cite this article:
Hsu C. Autophagy: A potential target for rescuing sepsis-induced hepatic failure.Chin J Physiol 2019;62:53-62


How to cite this URL:
Hsu C. Autophagy: A potential target for rescuing sepsis-induced hepatic failure. Chin J Physiol [serial online] 2019 [cited 2023 Nov 30 ];62:53-62
Available from: https://www.cjphysiology.org/text.asp?2019/62/2/53/257182


Full Text

 Sepsis – A Leading Cause of Mortality in Intensive Care Unit



Sepsis accounts for an estimated 30 million cases and 6 million deaths globally each year.[1] Multiple organ failure remains the most common cause of death for septic patients in intensive care units (ICUs). Despite the progress made in the clinical management, sepsis is still the leading cause of mortality and a major challenge in the critical care units.[2],[3] Early goal-directed therapy and improvements in supportive care (e.g., mechanical ventilation, fluid resuscitation, and broad-spectrum antibiotic coverage) have increased survival rate of patients with sepsis.[4] However, the increasing incidence of sepsis is predicted to continue as a result of an aging population, an increase in invasive medical procedures, the increased longevity of people with chronic diseases, spread of antibiotic-resistant organisms, and broader use of immunosuppressive and chemotherapeutic agents.[5]

Some specific treatments are available for treatment of sepsis such as active protein C, low dose corticosteroids, immunoglobulins and statins, HMGB1, antioxidant, carbon monoxide, and glycemic control.[6],[7],[8] However, international experts reviewed and updated the most recent and relevant scientific advances on severe sepsis. They found that with the failure of over 30 clinical trials, sepsis remains a great challenge in medicine.[9] This dilemma reflects our poor understanding of the responses in sepsis and the pressing need for new therapeutic approaches. In addition to blocking the inflammatory cascade, strategies focusing on host endogenous response to severe infection may give promise for improving outcomes in septic patients.

 The Liver Plays a Pivotal Role in Patient Survival Following Sepsis



The liver is responsible for over 200 functions, such as detoxification, storage, energy production, nutrient conversion, hormonal balance, and coagulation. These important physiological functions make the liver a critical organ for host survival following severe sepsis. In addition, liver is the first defense against bacteria from the gastrointestinal system, and hepatic dysfunction has an exceptional prognostic relevance for the course of sepsis.[10],[11],[12] Liver plays a central role in the host immune response to sepsis.[13] It represents a crucial conductor of antimicrobial response that contributes both to the clearance of pathogens and the triggers of immunosuppression that provide protection from an overwhelming immune response. A dysregulation of this complex interface leads to sepsis-induced liver injury and increased sepsis-related mortality. During sepsis, the liver injury progresses from hepatocellular dysfunction to liver damage and then to liver failure. Liver dysfunction often occurs in early sepsis such as 1.5 h after cecal ligation and puncture (CLP) in rodents or on the day of the sepsis diagnosis (<24 h postonset of the disease) in patients.[12] Ongoing inflammation and hypoperfusion cause liver damage and failure at late sepsis.[14] Clinical and experimental data suggest that early hepatic dysfunction is an independent risk factor for poor outcome in septic patients.[15] The mortality rate among septic patients with liver failure is higher than the mortality rate of septic patients with respiratory failure, which is the most common organ failure in sepsis.[16],[17] Attenuating liver injury and restoring liver function lowers morbidity and mortality rates in patients with sepsis.[13] These evidence have shown that liver failure directly contributes to disease progression and death in sepsis.[14] Hence, hepatic dysfunction substantially impairs the prognosis of sepsis and serves as a powerful independent predictor of mortality in the ICU. Thus, it is of great significance to investigate the pathogenesis and seek the effective treatment methods for septic liver failure.

 Pathogenesis of Sepsis-Induced Hepatic Failure



Sepsis usually develops as a result of the host response to infection and severe inflammation such as peritonitis. It is newly defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.[18] Sepsis is characterized by an overproduction of inflammatory cytokines such as tumor necrosis factor-alpha and interleukin 1. As a normal inflammatory response to septic insult, the production of cytokines is beneficial. However, an excessive inflammatory response associated with overproduction of reactive oxygen species (ROS) results in mitochondrial dysfunction and subsequent energetic failure.[2],[19],[20] The pathogenesis of organ dysfunction is multifactorial including cellular activation by circulating bacterial products, elaborated cytokines, disturbed perfusion of the microcirculation, systemic hypotension with subsequent tissue hypoperfusion, as well as direct tissue-toxicity caused by inflammatory immune reaction.[21] Disruptions in cell bioenergetics have been implicated in the pathogenesis of sepsis-induced organ failure. The exact mechanism behind the hypometabolic state is still a subject of debate but may involve a combination of impairment of the oxidative phosphorylation apparatus, damage to mtDNA, and dysregulations in cellular protective pathways. Despite the severe metabolic, hemodynamic and inflammatory stress, cells of failing organs accumulate damaged organelles, such as mitochondria[22],[23] and damaged misfolded proteins, which leads to endoplasmic reticulum (ER) stress.[24] Hepatic ER stress usually activates the unfolded protein response (UPR). With excessive ER stress, the UPR may fail, which promotes cellular dysfunction and cell death.[25],[26] Therefore, mitochondrial dysfunction, ER stress, and the UPR are potentially important contributors to sepsis-induced hepatic failure.

The liver is a target for sepsis-related injury, including hypoxic hepatitis due to ischemia and shock, cholestasis due to altered bile metabolism, hepatocellular injury due to overwhelming inflammation, as well as distinct pathologies such as secondary sclerosing cholangitis.[27] Increased serum bile acid concentrations observed in cholestatic conditions interfere with physiological processes and negatively influence organ function, resulting in impaired glucose and lipid metabolism, suppression of immune response, and vasodilatation.[28],[29] Bile-acid overload leads to increased oxidative stress, cell membrane permeability, impaired regeneration and retraction of bile transporters from the plasma membrane to the cytosol.[30],[31] In short, inadequate tissue perfusion and an overwhelming inflammatory response with pronounced cellular dysfunction, hallmarked by mitochondrial dysfunction and ER stress, are recognized as important contributors to the development of hepatic failure in sepsis.[32] However, interventions targeting these disturbances largely failed to improve patient outcome.[32] Hence, therapeutic options by stimulating cellular defense or protective mechanism such as autophagy, which performs crucial cell housekeeping and stress response functions, may open new therapeutic insights.

 Basic Functions of Autophagy in the Liver



Autophagy is an intracellular degradative pathway by which cells recycle cytoplasm and degrade excess or defective organelles for supplying energy and maintaining homeostasis under physiological condition.[33] There are three types of autophagy, macroautophagy, chaperone-mediated autophagy, and microautophagy. Most of our current knowledge is concentrated on macroautophagy (hereafter referred to as autophagy), which is the focus of this review. Liver or hepatocytes are thought to have higher levels of autophagy than other cell types because of their abundance of lysosomes and lysosomal enzymes. Basal liver autophagy plays an essential role in the turnover of intracellular organelles, degradation of long-lived cytosolic proteins, and damaged proteins.[34] During stress, the induced autophagy contributes to cell survival by supplying amino acids, glucose, and energy needed for cellular integrity. Impairing the biogenesis of mitochondria triggers autophagy,[35] which can be envisaged as a quality-control process aimed to prevent proliferation of defective mitochondria, and may even turn out to be a death program initiated when cells cannot recover from mitochondrial damage.[35] Meanwhile, amino acids released by autophagic degradation can be metabolized to produce glucose through gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. Therefore, hepatic autophagy plays a pivotal role in metabolic compensation.[36]

The liver is an organ highly dependent on autophagy for both normal function and prevention of the development of disease states due to the following unique properties. The liver is a mitochondria-enriched organ that produces glucose and stores fat for the whole body and autophagy regulates hepatic metabolism. Liver recycles the cellular proteins and glycogen to provide amino acids and glucose for generating adenosine triphosphate (ATP) when nutrient/growth factor depletion.[37] The hepatocytes are normally in a quiescent state and are particularly vulnerable to autophagy insufficiency that causes accumulation of excessively damaged organelles or oxidized proteins leading to cell injury. Moreover, the liver is the largest immune organ that directly receives the portal blood supply from the intestines and faces the continual challenge of exposure to ingested antigens or bacterial toxin such as lipopolysaccharide (LPS). Autophagy plays both roles in the sensing of infection and in the immune response.[38],[39] Autophagy serves a role in the removal of intracellular pathogens[40] and regulates the immune response in multiple ways, from assisting in antigen presentation to lymphocyte differentiation to the regulation of cytokine production and inflammation.[41],[42],[43] Moreover, hepatic autophagy also promotes cell survival through its basic function of degrading intracellular components. Taken together, functions of hepatic autophagy include balancing of energy and nutrients for basic cell functions, lipid metabolism, decision of cell fate, regulation of immune response, degradation of intracellular misfolded proteins,[33],[35] and the turnover of major subcellular organelles such as mitochondria, ER, and peroxisomes under both normal and pathophysiological conditions.[44]

 Role of Autophagy in Sepsis-Induced Hepatic Failure



The current understanding about the role of autophagy in the pathogenesis of sepsis remains limited and inconclusive. In clinical, genetic polymorphisms in the autophagy-related protein (ATG) 16 L1 and ATG human immunity-related GTPase affect the outcome of septic patients.[45],[46] Septic insult triggers autophagy in multiple organs including the liver.[47],[48],[49],[50] The human study indicates that considerable accumulation of autophagic vacuoles was observed in hepatocytes of postmortem liver specimens isolated from septic patients.[47] Moreover, the autophagic vacuolization increased in the hepatocytes is associated with mitochondrial injury.[47] Moreover, the activation of autophagy is clinically relevant because the lack of initiation of the autophagic response is associated with prolonged critical illness and lack of recovery from organ failure.[51] These findings support the notion that hepatic autophagy is involved in human sepsis.

Hepatic autophagy was activated in rodent sepsis models of CLP and LPS injection.[50],[52] Of these, the liver showed the highest level of autophagy induction, followed by heart and spleen.[53] The result from rodent models of sepsis showed the putative role of autophagy in organ failure during sepsis [Table 1]. The result showed that the number of autophagosomes was increased and inhibition of autophagy process by chloroquine immediately after CLP resulted in elevated serum transaminase levels.[53] Moreover, the inhibition of autophagy by blocking vacuolar sorting protein 34, a central protein in promoting autophagic signaling, exaggerates liver dysfunction in septic mice.[54] In addition, mice with a hepatocyte-specific knockout of Atg7 are sensitized to LPS-induced hepatocyte death suggesting that autophagy serves a critical function in the resistance to LPS-induced liver injury.[55] Moreover, blocking hepatic autophagy accelerates mitochondrial damage and time to mortality in the murine sepsis model, suggesting that liver autophagy plays a protective role for organ failure due to severe sepsis.[56] The protective nature of the autophagic process is further documented by using complementary autophagic antagonistic (Atg7 siRNA) versus agonistic (rapamycin) treatment.[49],[53] However, a recent publication showed that mouse model challenged with LPS or CLP combined with 3-MA displayed increased survival after endotoxemia, LPS combined with rapamycin worsened the endotoxic shock of the mice, supporting autophagy as a maladaption during sepsis.[57] The discrepancy of these observations may be due to the differences in experimental settings, in which the severity of sepsis, drug specificity, and timing of delivery differed. In addition, since sepsis shows a biphasic changes in hemodynamic, metabolic, and immune response, the dynamic alterations of autophagy during the progression of sepsis cannot be ignored.{Table 1}

 Kinetic Changes of Autophagy in Liver during Sepsis



Interestingly, results from dynamic studies showed that autophagy transiently increases on septic insult and is followed by a suppression of autophagy.[48],[49],[50] Evidence shows that hepatic autophagy is induced during the initial 4 h after CLP but declines after this point until 24 h.[49],[53],[54],[58],[59] The previous study showed that microtubule-associated protein 1 light chain 3 (LC3), a marker of autophagosome formation, transiently increases in liver at the early stage of sepsis (3 h after CLP). While a suppression of autophagy associated with significant liver dysfunction at late sepsis (9–18 h after CLP) was observed.[48],[49] This result showed that autophagic activity is elevated during the early hyperdynamic phase followed by a declination at late hypodynamic stage of sepsis.[49],[53],[58],[60] Based on the time course changes of autophagy during sepsis, the late stage exhaustion of autophagic activity is associated with hepatic dysfunction, inflammatory dysregulation, histological injury, mitochondrial dysfunction, and apoptosis. Given multiple roles of autophagy in maintaining mitochondrial integrity,[61] controlling cytokine release,[62] eradicating bacteria,[63] and neutralizing microbial toxins,[64] the autophagy suppression at late stage of sepsis may be a leading cause of hepatic failure and poor outcome. The progression of sepsis into immunosuppression also can be explained by the role of autophagy in maintaining survival and proliferation of T-lymphocytes.[65] A recent study further finds that restoring impaired autophagic flux by genipin and sinomenine protects against septic liver injury.[66],[67] Therefore, it is possible that transient autophagy induction at early sepsis is not enough to protect the liver from injury during severe inflammation. Although contradictory findings have been reported, autophagy inductions could be beneficial or detrimental depending on type and stage of the pathological conditions of diseases.[68],[69] In sum, evidence from in vitro and in vivo studies favors a protective role of hepatic autophagy in sepsis.[53],[70] It makes autophagy an attractive target for therapeutic manipulation after sepsis. Thus, maintaining or augmenting constitutive levels of autophagy may be an important therapeutic strategy. In addition, elimination of the factors that suppress hepatic autophagy may prevent hepatic failure at late sepsis.

 Possible Factors Contribute to Autophagy Suppression at Late Sepsis



A great number of extracellular stimuli (starvation, insulin, and growth factor) and intracellular stimuli (ROS production, accumulation of misfolded proteins, damaged mitochondria, energetic failure, and microorganism invasion) are able to modulate the autophagic response. Among these factors, which factor suppresses hepatic autophagy during sepsis remains uncertain. The previous study showed that preadministration of glucose to mice after starvation increased plasma insulin and inhibited autophagy, indicating the plasma high glucose-induced insulin exerted a suppressive effect on liver autophagy.[71] In mouse and rat CLP models of sepsis, hyperinsulinemia was observed in the initial 3 and 5 h, respectively. While a suppression of autophagy (9–18 h after CLP), following hyperinsulinemia (5 h after CLP) was observed in septic rats.[48],[49] The previous report indicated that binding of insulin with its receptor leads to phosphoinositide 3-kinase-AKT activation and inactivation of the tuberous sclerosis complex 1 (TSC1)-TSC2 which, in turn, releases inhibition of RHEB that then activates mammalian target of rapamycin (mTOR).[72] Since, active mTOR inhibits autophagy through phosphorylating unc-51-like kinase 1 (ULK1; the autophagy initiating kinase, also known as ATG-1),[36],[73],[74] and rapamycin, an mTOR inhibitor, reverses autophagy suppression by insulin, suggesting that mTOR mediates the suppression of autophagy by hyperinsulinemia.[75] Therefore, early hyperinsulinemia and downstream mTOR signaling may contribute to the suppression of hepatic autophagy at late sepsis.

Except for hyperinsulinemia, sepsis-induced hyperglycemia, when present over prolonged time, is associated with oxidative stress,[76] which causes mitochondrial dysfunction and cellular energetic failure that contributes to the development of the multiple organ failure.[77],[78],[79] A crucial intracellular sensor of energy status is 5' adenosine monophosphate-activated protein kinase (AMPK), which controls mitochondrial biogenesis by the activation of peroxisome proliferator-activated receptor-γ coactivator-α and disposal of defective organelles by autophagy.[80] In addition, AMPK induces autophagy by inhibiting the mTOR pathway[81] and by controlling gene expression of ATG proteins.[82] AMPK consists of a catalytic α-subunits (-α1 and -α2) and regulating subunits-2 β and –γ and is activated by high levels of adenosine 5′-monophosphate (AMP) and low levels of ATP.[81] In rodent CLP model, levels of AMP were significantly increased after CLP.[83] Another report indicated that, during sepsis, liver injury in mice is associated with a dysregulation of AMPK activation and its downstream metabolic pathways. AMPK-dependent pathways of autophagy and mitochondrial biogenesis were also impaired in mice subjected to polymicrobial sepsis.[84] The fact that AMPKα1 gene deletion in septic mice associated with increased susceptibility to sepsis-induced liver injury suggests that AMPK is an important modulator of the metabolic response in sepsis.[84] Moreover, activation of AMPK was protective, and AICAR (AMPK analog) minimized organ injury by decreasing inflammatory cytokines and endothelial activation. These data suggest that AMPK signaling influences sepsis-induced endothelial activation and organ injury.[85] However, whether the impairment of AMPK may also lead to the suppression of hepatic autophagy during sepsis needs further investigation.

 Therapeutic Strategies Targeting Autophagy De-Suppression for Septic Liver



In mammalian, there are a number of signaling complexes and pathways involved in the initiation and maturation of autophagy. At signal transduction (posttranslational) level, mTOR (a serine/threonine kinase) is involved in most regulatory pathways that control the response to changes in nutrient conditions and energy metabolism. However, there are still many unanswered questions regarding the regulation of the mTOR signaling network under a severe inflammation.[86] The mTOR functions as a key homeostatic regulator of cell growth and orchestrates whether anabolic or catabolic reactions are favored. It is integral to two distinct cellular complexes, termed mTOR complex 1 (mTORC1) and mTORC2. The mTORC1 plays a key anabolic role in promoting cell growth and proliferation. In conditions of nutrient and energy sufficiency, mTORC1 is active and inhibits the initiation of autophagy through phosphorylating ULK1 (unc-51-like kinase 1) at Ser757.[87] When cellular energy levels are low, AMPK binds to and activates ULK1 through phosphorylation at Ser317, Ser777, or Ser555.[88],[89],[90] Revealing a feedback mechanism, phosphorylation of ULK1 by mTORC1 was shown to impede the ability of AMPK to activate ULK1.

In addition to the direct phosphorylation of ULK1, mTORC1 inhibits nuclear localization of the transcription factor EB (TFEB), a member of the bHLH leucine-zipper family of transcription factors that drives expression of ATG genes.[91] TFEB works in conjunction with ZKSCAN3 (a zinc finger family DNA-binding protein) that acts as a transcriptional repressor of autophagy.[92] Insulin signaling may suppress hepatic autophagy through activating mTOR,[93] which also inhibits nuclear translocation of TFEB and subsequently suppresses autophagy. The previous report has shown that protein kinase C (PKC) activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its translocation out of the nucleus.[94] According to the previous report, both the activity and expression of hepatic PKCα are decreased during sepsis.[95] Therefore, PKC inactivation after CLP may increase the level of nuclear ZKSCAN3, which suppresses the expression of ATG genes. These results support the involvement of the transcriptional regulations of ZKSCAN3 and TFEB in autophagy suppression during sepsis.

Recent studies have unveiled a transcriptional and epigenetic network that regulates autophagy.[96] The expression of ATG genes can be regulated by several epigenetic mechanisms, i.e., chromatin modulation, histone modification, and microRNAs. Among the histone-modifying enzymes, the H3K9 methyltransferase G9a is thought to act as a repressor of ATG genes, i.e., ulk1, wipi1, atg9, LC3b, and p62.[97],[98] G9a directly associates with genes known to participate in the autophagic process, and epigenetically repressing them under basal condition.[99] When autophagy is induced, G9a leaves the promotors and allows demethylation of H3K9, resulting in increased transcription of autophagy genes.[98],[100] Therefore, the inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy induction.[98] The highly overlapping of target genes between G9a and ZKSCAN3/TFEB suggesting that G9a may participate in the epigenetic silencing on autophagy-related genes. As a whole, we prospect that delineation of autophagy regulation at signal transduction, transcriptional and epigenetic levels may help the development of short-term and long-term management for balancing between demand and supply of autophagy under sepsis [Figure 1].{Figure 1}

 Current Use Autophagy Inducers



Because autophagy dysregulation may underlie the pathogenesis of liver failure in sepsis, specific autophagy inducing agents [Table 2] may have the potential for the prevention and treatment of sepsis-induced hepatic failure.[101] Some drugs in clinical use are capable of augmenting autophagy; however, these compounds exert pleiotropic effects, revealing an unmet need to develop specific inducers of autophagy. Therefore, in-depth studies are needed to select the best therapeutic strategy for hepatic failure in sepsis.{Table 2}

 Conclusion and Perspectives



Sepsis-induced organ failure remains a major problem in critical care medicine. Autophagy has a Janus-face in that being primarily a survival mechanism and it can also lead to autophagic cell death under certain conditions. However, in sepsis, it seems clear that one of the major functions of autophagy is to fight to keep cells alive under stressful “life-threatening” conditions. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and in the pathophysiology of sepsis with the intent of furthering the development of autophagy-based therapies for hepatic failure in human polymicrobial sepsis. Previous in vitro and in vivo studies demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment, which contributes to hepatic failure. Future investigations are likely to further elucidate whether the early hyperinsulinemia suppresses autophagy at late sepsis through Akt/mTOR pathway and/or through regulation of ATG genes at both transcriptional and epigenetic levels.

Taking into account the crucial role of autophagy in hepatic failure and the existence of therapies aimed at signaling transduction (posttranslational), transcriptional, and epigenetic levels makes therapeutic strategies targeting autophagy possible in a near future. Experimental data suggest that targeting autophagy induction results in liver protection and offer survival advantage. However, it also underscores that the effect of targeting these mechanistic pathways on short- and long-term outcomes depends highly on the timing of therapeutic intervention. In moving forward, efforts to understand the adaptive or maladaptive character of autophagy in multiple organs, to discover phase-specific biomarkers to guide therapy, to develop a combination therapy of autophagy inducers with different action site to overcome feedback regulation of autophagic machinery will provide a translational gateway, and an opportunity to improve septic patient outcomes.

Financial support and sponsorship

This work was supported by Ministry of Science and Technology, Taiwan, ROC (MOST 106-2320-B-037-013-MY3).

Conflicts of interest

There are no conflicts of interest. [145]

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