Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

Santori, Fabio R.; Huang, Peiying; Pavert, Serge A. van de; Douglass, Eugene F.; Leaver, David J.; Haubrich, Brad A.; Keber, Rok; Lorbek, Gregor; Konijn, Tanja; Rosales, Brittany N.; Rozman, Damjana; Horvat, Simon; Rahier, Alain; Mebius, Reina E.; Rastinejad, Fraydoon; Nes, W. David; Littman, Dan R.

doi:10.1016/j.cmet.2015.01.004

Cited by 198 publications

(240 citation statements)

References 47 publications

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“…2G). NSDHL has been reported to influence immune cell maturation, raising the possibility of a non-cell autonomous action in promoting through tumor growth through influencing microenvironment (Santori et al, 2015; Villablanca et al, 2010). However, we did not detect significant differences in infiltration by inflammatory cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

et al. 2015

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Summary Meiosis activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by EGFR or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRASG12D. Strikingly, Nsdhl inactivation antagonized the growth of skin tumors, while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, while an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.

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Section: Resultsmentioning

confidence: 99%

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

et al. 2015

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“…However, other lipid metabolic genes are induced in an SREBP1c-independent manner in the HDAC3 knockout livers, which are steatotic (Feng et al 2011;Sun et al 2012;Papazyan et al 2016a). In addition, cholesterol and cholesterol derivatives have been cocrystallized with RORα and have been suggested to be ROR ligands that regulate ROR activities (Kojetin and Burris 2014;Santori et al 2015). Interestingly, SREBP is also a major regulator of cholesterol synthesis, and its activity is inhibited by high levels of cholesterol .…”

Section: Discussionmentioning

confidence: 99%

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

et al. 2017

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Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders.

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“…Among postsqualene metabolites, activation of LXR by endogenous oxysterols regulates various aspects of cholesterol homeostasis (Janowski et al, 1996;Janowski et al, 1999;Wong et al, 2008;Zhao and DahlmanWright, 2010) whereas methyl sterols, produced from lanosterol have meiosis-stimulating activity (Byskov et al, 1995). Finally, desmosterol and other postsqualene metabolites have been linked to T H 17 lymphocyte differentiation through activation of retinoic acid-related orphan receptor g (Hu et al, 2015;Santori et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

Rondini

Pant

Kocarek

2015

J Pharmacol Exp Ther

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Cytosolic sulfotransferase 1C2 (SULT1C2) is expressed in the kidney, stomach, and liver of rats; however, the mechanisms regulating expression of this enzyme are not known. We evaluated transcriptional regulation of SULT1C2 by mevalonate (MVA)-derived intermediates in primary cultured rat hepatocytes using several cholesterol synthesis inhibitors. Blocking production of mevalonate with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin (30 mM), reduced SULT1C2 mRNA content by ∼40% whereas the squalene synthase inhibitor squalestatin (SQ1, 0.1 mM), which causes accumulation of nonsterol isoprenoids, increased mRNA content by 4-fold. Treatment with MVA (10 mM) strongly induced SULT1C2 mRNA by 12-fold, and this effect was blocked by inhibiting squalene epoxidase but not by more distal cholesterol inhibitors, indicating the effects of MVA are mediated by postsqualene metabolites. Using rapid amplification of cDNA ends (RACE), we characterized the 59 end of SULT1C2 mRNA and used this information to generate constructs for promoter analysis. SQ1 and MVA increased reporter activity by ∼1.6-and 3-fold, respectively, from a construct beginning 49 base pairs (bp) upstream from the longest 59-RACE product (-3140:-49). Sequence deletions from this construct revealed a hepatocyte nuclear factor 1 (HNF1) element (-2558), and mutation of this element reduced basal (75%) and MVA-induced (30%) reporter activity and attenuated promoter activation following overexpression of HNF1a or 1b. However, the effects of SQ1 were localized to a more proximal promoter region (-281:-49). Collectively, our findings demonstrate that cholesterol biosynthetic intermediates influence SULT1C2 expression in rat primary hepatocytes. Further, HNF1 appears to play an important role in mediating basal and MVA-induced SULT1C2 transcription.

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Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

Cited by 198 publications

References 47 publications

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

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