title: The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism.
abstract: Autophagy plays a critical role in cell survival from prolonged starvation and recycling of aggregated proteins and damaged organelles. One of the essential genes involved in the autophagic initiation is autophagy-related 14 (Atg14), also called Barkor for Beclin 1-associated autophagy-related key regulator. Although its crucial role in the autophagic process has been reported, the gene regulation of Atg14 and its metabolic functions remain unclear. In this work we have identified that the Atg14 gene is regulated by forkhead box O (FoxO) transcription factors and circadian rhythms in the mouse liver. Luciferase reporter analyses and chromatin immunoprecipitation assays have revealed well conserved cis-elements for FoxOs and Clock/Bmal1 in the proximal promoter of the Atg14 gene. To examine the functions of hepatic Atg14, we have performed the gene knockdown and overexpression in the mouse livers. Remarkably, knockdown of Atg14 leads to elevated levels of triglycerides in the liver and serum as well. Conversely, overexpression of Atg14 improves hypertriglyceridemia in both high fat diet-treated wild-type mice and FoxO1/3/4 liver-specific knock-out mice. In summary, our data suggest that Atg14 is a new target gene of FoxOs and the core clock machinery, and this gene plays an important role in hepatic lipid metabolism.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Xiong
authors.forename: Rongya
authors.initials: R
authors.lastname: Tao
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: X Charlie
authors.initials: XC
authors.lastname: Dong
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D002940:Circadian Rhythm / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D014280:Triglycerides / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: C539000:ATG14 protein, human; D033942:Adaptor Proteins, Vesicular Transport; C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D051858:Forkhead Transcription Factors; D008055:Lipids; D014280:Triglycerides; D033921:Vesicular Transport Proteins