PAS Kinase Drives Lipogenesis through SREBP-1 Maturation

Wu, Xiaoying; Romero, Donna; Światek, Wojciech; Dorweiler, Irene; Kikani, Chintan K.; Sabic, Hana; Zweifel, Ben S.; McKearn, John P.; Blitzer, Jeremy T.; Nickols, G. Allen; Rutter, Jared

doi:10.1016/j.celrep.2014.06.006

Cited by 39 publications

(54 citation statements)

References 47 publications

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“…Former observations have reported that inhibiting several regulators (including FAS, SREBP-1C) hinders liver lipid deposition in obesity and its associated symptoms [43][44][45]. In this study, we found that S100A4 deficiency caused elevated accumulation of liver fat, and that led to elevated CHO and TG (Fig.…”

Section: Discussionsupporting

confidence: 53%

S100A4 protects mice from high-fat diet-induced obesity and inflammation

Hou

Jiao

et al. 2018

Laboratory Investigation

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As a member from S100 calcium-binding protein family, S100A4 is ubiquitous and elevated in tumor progression and metastasis, but its role in regulating obesity has not been well characterized. In this study, we showed that S100A4 was mainly expressed by stromal cells in adipose tissue and the S100A4 level in adipose tissue was decreased after high-fat diet (HFD). S100A4 deficient mice exhibited aggravated symptoms of obesity and suppressed insulin signaling after 12 weeks of HFD. Aggravated obesity in S100A4 deficient mice were found to be positively correlated with higher inflammatory status of the liver. Then, we found that extracellular S100A4 or overexpressed S100A4 inhibited adipogenesis and decreased mRNA levels of inflammation gene in 3T3-L1 adipocytes in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 displayed the opposite results. Additionally, the protective effect induced by S100A4 during HFD-induced obesity was tightly related with activation of Akt signaling in adipose tissues, as well as livers and muscles. Taken together, we demonstrate that S100A4 is an inhibitory factor for obesity and attenuates the inflammatory reaction, while activating the Akt signaling, which suggest that S100A4 is a potential candidate for the treatment of diet-induced obesity and its complications.

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Section: Discussionsupporting

confidence: 53%

S100A4 protects mice from high-fat diet-induced obesity and inflammation

Hou

Jiao

et al. 2018

Laboratory Investigation

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“…3A). Interestingly, the WT PASK associated with KD mTOR showed significantly diminished phosphorylation at Thr 307 , which is an autophosphorylation site that we have shown previously to be a reliable marker of PASK activity (31). Thus, expression of KD mTOR suppresses PASK activity in a dominant negative manner in cells.…”

Section: Pask Is Phosphorylated By Mtorc1 At Multiple Residues To Stimentioning

confidence: 55%

Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

Kikani

Fogarty

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiationcommitted progenitors (early stage of differentiation, marked by the induction of myogenin expression), myotube fusion, and, ultimately, hypertrophy (later stage of differentiation). While a major mTORC1 substrate, p70S6K, is required for myotube fusion and hypertrophy, an mTORC1 effector for the induction of myogenin expression remains unclear. Here, we identified Per-Arnt-Sim domain kinase (PASK) as a downstream phosphorylation target of mTORC1 in MuSCs during differentiation. We have recently shown that the PASK phosphorylates Wdr5 to stimulate MuSC differentiation by epigenetically activating the myogenin promoter. We show that phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exit from self-renewal, and induction of the myogenesis program. Our studies reveal that mTORC1-PASK signaling is required for the rise of myogenin-positive committed myoblasts (early stage of myogenesis), whereas mTORC1-S6K signaling is required for myoblast fusion (later stage of myogenesis). Thus, our discoveries allow molecular dissection of mTOR functions during different stages of the myogenesis program driven by two different substrates. mTOR | PASK | myogenin | muscle stem cell | Pax7

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“…Such a concept is supported by the results of recent studies on SREBP inhibitors in animal models [43][44][45][46]. Here, we briefly describe the SREBP maturation pathway, elaborate key molecular mechanisms involved in the classical triad of hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, and discuss beneficial effects of four SREBP inhibitors as well as potential caveats associated with their use.…”

mentioning

confidence: 88%

“…Pharmacological inhibition of PASK was utilized to inhibit SREBP-1 activity in the third study [45]. Earlier research had shown that protection from HFD-induced liver steatosis is a main phenotype of Pask -/-mice [41].…”

Section: Pask Inhibitorsmentioning

confidence: 99%