Author Correction: Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan

Wang, Chensu; Niederstrasser, Hanspeter; Douglas, Peter M.; Lin, Rueyling; Jaramillo, Juan David Vasquez; Li, Yang; Oswald, Nathaniel W.; Zhou, Anwu; McMillan, Elizabeth A.; Mendiratta, Saurabh; Wang, Zhaohui; Zhao, Tian; Lin, Zhiqaing; Luo, Min; Huang, Gang; Brekken, Rolf A.; Posner, Bruce A.; MacMillan, John B.; Gao, Jinming; White, Michael A.

doi:10.1038/s41467-018-04519-8

Cited by 4 publications

(3 citation statements)

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“…A growing body of evidence indicates that TFEB can be regulated by phosphorylation with a variety of kinases, including mTORC1, GSK-3β, ERK2, PKCβ, and MAP4K3 34 , 54 . Small agonists of the TFEB pathway have been shown to ameliorate metabolic syndrome and extend the lifespan in mice and C. elegans , respectively 55 . Therefore, the activity of TFEB could be regulated by an agonist or a specific inhibitor or kinase activator, making TFEB an attractive therapeutic target for neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

A splicing variant of TFEB negatively regulates the TFEB-autophagy pathway

Park

Sohn

Koh

et al. 2021

Sci Rep

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Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosomal pathway (ALP). Here, we cloned a novel splicing variant of TFEB, comprising 281 amino acids (hereafter referred to as small TFEB), and lacking the helix-loop-helix (HLH) and leucine zipper (LZ) motifs present in the full-length TFEB (TFEB-L). The TFEB variant is widely expressed in several tissues, including the brain, although its expression level is considerably lower than that of TFEB-L. Intriguingly, in cells stably expressing small TFEB, the expression profile of genes was inverted compared to that in cells ectopically expressing TFEB-L. In addition, fisetin-induced luciferase activity of promoter containing either coordinated lysosomal expression and regulation (CLEAR) element or antioxidant response element (ARE) was significantly repressed by co-transfection with small TFEB. Moreover, fisetin-mediated clearance of phosphorylated tau or α-synuclein was attenuated in the presence of small TFEB. Taken together, the results suggest that small TFEB is a novel splicing variant of TFEB that might act as a negative regulator of TFEB-L, thus fine tuning the activity of ALP during cellular stress.

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Section: Discussionmentioning

confidence: 99%

A splicing variant of TFEB negatively regulates the TFEB-autophagy pathway

Park

Sohn

Koh

et al. 2021

Sci Rep

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“…A comprehensive study by Wang et al (2018) used a nanotechnology-enabled high throughput screen to test 15,000 compounds to identify those that activate TFEB. Three of these, digoxin, a cardiac glycoside used to treat atrial fibrillation, ikarugamycin, a natural antibacterial/anti-protozoan agent, used to treat infections, and alexidine dihydrochloride, an inhibitor of protein tyrosine phosphatase localized to the mitochondrion, activated TFEB, each by a distinct calcium-dependent mechanism.…”

Section: Actions and Agents That Alleviate Ethanol-induced And/or Diementioning

confidence: 99%

“…Finally, evidence, mostly from animal studies, but some human studies, suggest that caffeine/coffee, resveratrol, corosolic acid, zinc, carbamazepine, and rapamycin, individually activate autophagy/lipophagy and may also be used to prevent and treat alcohol-induced fatty liver. The clinical utility of these aforementioned compounds and of those tested recently (Wang et al, 2018) appear to have therapeutic promise but those that were most recently discovered to activate TFEB (Wang et al, 2018) must be tested for safety and efficacy in human trials.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Lipophagy and Alcohol-Induced Fatty Liver

Yang

Thomes

et al. 2019

Front. Pharmacol.

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This review describes the influence of ethanol consumption on hepatic lipophagy, a selective form of autophagy during which fat-storing organelles known as lipid droplets (LDs) are degraded in lysosomes. During classical autophagy, also known as macroautophagy, all forms of macromolecules and organelles are sequestered in autophagosomes, which, with their cargo, fuse with lysosomes, forming autolysosomes in which the cargo is degraded. It is well established that excessive drinking accelerates intrahepatic lipid biosynthesis, enhances uptake of fatty acids by the liver from the plasma and impairs hepatic secretion of lipoproteins. All the latter contribute to alcohol-induced fatty liver (steatosis). Here, our principal focus is on lipid catabolism, specifically the impact of excessive ethanol consumption on lipophagy, which significantly influences the pathogenesis alcohol-induced steatosis. We review findings, which demonstrate that chronic ethanol consumption retards lipophagy, thereby exacerbating steatosis. This is important for two reasons: (1) Unlike adipose tissue, the liver is considered a fat-burning, not a fat-storing organ. Thus, under normal conditions, lipophagy in hepatocytes actively prevents lipid droplet accumulation, thereby maintaining lipostasis; (2) Chronic alcohol consumption subverts this fat-burning function by slowing lipophagy while accelerating lipogenesis, both contributing to fatty liver. Steatosis was formerly regarded as a benign consequence of heavy drinking. It is now recognized as the “first hit” in the spectrum of alcohol-induced pathologies that, with continued drinking, progresses to more advanced liver disease, liver failure, and/or liver cancer. Complete lipid droplet breakdown requires that LDs be digested to release their high-energy cargo, consisting principally of cholesteryl esters and triacylglycerols (triglycerides). These subsequently undergo lipolysis, yielding free fatty acids that are oxidized in mitochondria to generate energy. Our review will describe recent findings on the role of lipophagy in LD catabolism, how continuous heavy alcohol consumption affects this process, and the putative mechanism(s) by which this occurs.

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