Rapamycin up-regulates triglycerides in hepatocytes by down-regulating Prox1

Kwon, Sora; Jeon, Ji-Sook; Kim, Su Bin; Hong, Young‐Kwon; Ahn, Curie; Sung, Jung‐Suk; Choi, Inho

doi:10.1186/s12944-016-0211-x

Cited by 14 publications

(12 citation statements)

References 32 publications

(41 reference statements)

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“…Hence, a conserved epigenetic module links metabolic reprogramming with increased protection against hepatic steatosis and insulin resistance in Ames dwarf and DR mice. Rapamycin, in contrast, activates hepatic lipid metabolism [135,136] and shares only a small subset of regulated transcripts with DR [137], which is in line with hypomethylation of genes involved in lipid and fatty acid metabolism (compare S5A and S5B Fig). These opposite methylation changes might also explain the higher number of hypomethylated DMRs under rapamycin treatment and the weak overlap with DR.…”

Section: Discussionsupporting

confidence: 61%

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

et al. 2018

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Dietary, pharmacological and genetic interventions can extend health-and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, wholegenome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

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Section: Discussionsupporting

confidence: 61%

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

et al. 2018

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“…Furthermore, SIRT1 enhances thyroid (T 3 ) control over expression of several lipogenic genes, including CPT1A , PPARA , PPARGC1A, PDK4, PCK1 and SREBP-1c [ 59 ]. Another transcription factor up-regulated in liver of embryos was prospero-related homeobox 1 ( PROX1 ), which is important for hepatic embryogenesis and a negative regulator of triglyceride synthesis via mTOR signaling [ 60 ]. Thus, the metabolism of the late chicken embryo is under the intricate control of multiple transcription factors and directed at utilization of yolk lipids that amass in liver.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of liver during the critical embryo-to-hatchling transition period in the chicken (Gallus gallus)

et al. 2018

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BackgroundAlthough hatching is perhaps the most abrupt and profound metabolic challenge that a chicken must undergo; there have been no attempts to functionally map the metabolic pathways induced in liver during the embryo-to-hatchling transition. Furthermore, we know very little about the metabolic and regulatory factors that regulate lipid metabolism in late embryos or newly-hatched chicks. In the present study, we examined hepatic transcriptomes of 12 embryos and 12 hatchling chicks during the peri-hatch period—or the metabolic switch from chorioallantoic to pulmonary respiration.ResultsInitial hierarchical clustering revealed two distinct, albeit opposing, patterns of hepatic gene expression. Cluster A genes are largely lipolytic and highly expressed in embryos. While, Cluster B genes are lipogenic/thermogenic and mainly controlled by the lipogenic transcription factor THRSPA. Using pairwise comparisons of embryo and hatchling ages, we found 1272 genes that were differentially expressed between embryos and hatchling chicks, including 24 transcription factors and 284 genes that regulate lipid metabolism. The three most differentially-expressed transcripts found in liver of embryos were MOGAT1, DIO3 and PDK4, whereas THRSPA, FASN and DIO2 were highest in hatchlings. An unusual finding was the “ectopic” and extremely high differentially expression of seven feather keratin transcripts in liver of 16 day embryos, which coincides with engorgement of liver with yolk lipids. Gene interaction networks show several transcription factors, transcriptional co-activators/co-inhibitors and their downstream genes that exert a ‘ying-yang’ action on lipid metabolism during the embryo-to-hatching transition. These upstream regulators include ligand-activated transcription factors, sirtuins and Kruppel-like factors.ConclusionsOur genome-wide transcriptional analysis has greatly expanded the hepatic repertoire of regulatory and metabolic genes involved in the embryo-to-hatchling transition. New knowledge was gained on interactive transcriptional networks and metabolic pathways that enable the abrupt switch from ectothermy (embryo) to endothermy (hatchling) in the chicken. Several transcription factors and their coactivators/co-inhibitors appear to exert opposing actions on lipid metabolism, leading to the predominance of lipolysis in embryos and lipogenesis in hatchlings. Our analysis of hepatic transcriptomes has enabled discovery of opposing, interconnected and interdependent transcriptional regulators that provide precise ying-yang or homeorhetic regulation of lipid metabolism during the critical embryo-to-hatchling transition.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5080-4) contains supplementary material, which is available to authorized users.

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“…The findings reflect changes in the amount of Prox1 and VEGFR-3 per cell and in the total number of lymphatic endothelial cells. Rapamycin downregulates expression of VEGFR-3 in lymphatic endothelial cells in vitro (65) and Prox1 in mouse liver (76).…”

Section: Attributes and Limitations Of The Ccsp/vegf-c Mouse Model Ofmentioning

confidence: 99%

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Bałuk¹,

Yao²,

Flores³

et al. 2017

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Rapamycin up-regulates triglycerides in hepatocytes by down-regulating Prox1

Cited by 14 publications

References 32 publications

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

Transcriptional profiling of liver during the critical embryo-to-hatchling transition period in the chicken (Gallus gallus)

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

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