Autophagy regulates lipid metabolism

Singh, Rajat; Kaushik, Susmita; Wang, Yongjun; Xiang, Youqing; Novak, Inna; Komatsu, Masaaki; Tanaka, Keiji; Cuervo, Ana María; Czaja, Mark J.

doi:10.1038/nature07976

Cited by 3,303 publications

(3,577 citation statements)

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“…Evidence is also available indicating that excessive steatosis and fibrosis dramatically inhibited hepatic function in various pathological conditions including aging (Kuk et al., 2009). More importantly, autophagy has been reported to be linked to lipid metabolism (Liu & Czaja, 2013; Liu, Guo, et al., 2016; Singh et al., 2009; Yang, Li, Fu, Calay, & Hotamisligil, 2010). Intracellular lipids regulate levels of autophagy, and inhibition of autophagy increases hepatic lipid storage in cultured hepatocytes and mouse liver during starvation (Liu & Czaja, 2013).…”

Section: Discussionmentioning

confidence: 99%

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

et al. 2017

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SummaryRecent studies showing the therapeutic effect of young blood on aging‐associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging‐associated organ injuries, this study was designed to determine the effect of young blood on aging‐induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy. Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 weeks, and 3‐methyladenine or wortmannin was used to inhibit young blood‐induced autophagy. Aging was associated with elevated levels of alanine transaminase and aspartate aminotransferase, lipofuscin accumulation, steatosis, fibrosis, and defective liver regeneration after partial hepatectomy, which were significantly attenuated by young plasma injections. Young plasma could also restore aging‐impaired autophagy activity. Inhibition of the young plasma‐restored autophagic activity abrogated the beneficial effect of young plasma against hepatic injury with aging. In vitro, young serum could protect old hepatocytes from senescence, and the antisenescence effect of young serum was abrogated by 3‐methyladenine, wortmannin, or small interfering RNA to autophagy‐related protein 7. Collectively, our data indicate that young plasma could ameliorate age‐dependent alterations in hepatic function partially via the restoration of autophagy.

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Section: Discussionmentioning

confidence: 99%

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

et al. 2017

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“…Another mechanism recently identified to play a key role in the regulated metabolism of hepatic LDs is autophagy, a lysosome‐driven catabolic process that can specifically target cellular cargo and organelles for breakdown 13. Evidence supports a role for EtOH intake in altered hepatic autophagy.…”

Section: Introductionmentioning

confidence: 99%

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Schulze¹,

Rasineni

Weller³

et al. 2017

Hepatology Communications

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Alcohol consumption is a well‐established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol‐induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. Nutrient starvation results in Rab7 activation on the surface of the LD and lysosomal compartments, resulting in the mobilization of triglycerides stored within the LDs for energy production. Here, we examine whether the steatotic effects of alcohol exposure are a result of perturbations to the Rab7‐mediated lipophagic pathway. Rats chronically fed an ethanol‐containing diet accumulated significantly higher levels of fat in their hepatocytes. Interestingly, hepatocytes isolated from these ethanol‐fed rats contained juxtanuclear lysosomes that exhibited impaired motility. These changes are similar to those we observed in Rab7‐depleted hepatocytes. Consistent with these defects in the lysosomal compartment, we observed a marked 80% reduction in Rab7 activity in cultured hepatocytes as well as a complete block in starvation‐induced Rab7 activation in primary hepatocytes isolated from chronic ethanol‐fed animals. Conclusion: A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting, and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis. (Hepatology Communications 2017;1:140‐152)

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“…Autophagy plays a major role in systemic metabolic homeostasis [39] and hepatic lipid metabolism [40]. Moreover, hepatocytes have been reported to exhibit MAPK8/9-dependent autophagy [6].…”

Section: Resultsmentioning

confidence: 99%

Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy

et al. 2018

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Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more complex than previously considered.Abbreviations: AKT: thymoma viral proto-oncogene;ALB: albumin; ATG4: autophagy related 4; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine diphosphate; DMEM: Dulbecco’s modified Eagle’s medium; EDTA: ethylenediaminetetraacetic acid; EBSS: Earle’s balanced salt solution; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HRAS: Harvey rat sarcoma virus oncogene; IgG: Immunoglobulin G; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK1: mitogen-activated protein kinase 8; MAPK9/JNK2: mitogen-activated protein kinase 9; MAPK10/JNK3: mitogen-activated protein kinase 10; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; RPS6KB1/p70: ribosomal protein S6 kinase, polypeptide 1; PPARA: peroxisome proliferator activated receptor alpha; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; TRP53: transforming related protein 53; TUBA: tubulin alpha; UV: ultraviolet; WT: wild-type

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Autophagy regulates lipid metabolism

Cited by 3,303 publications

References 38 publications

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy

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Autophagy regulates lipid metabolism

Cited by 3,303 publications

References 38 publications

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7

Role of the MAPK/cJun NH 2 -terminal kinase signaling pathway in starvation-induced autophagy

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Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy