mTORC2 Promotes Tumorigenesis via Lipid Synthesis

Guri, Yakir; Colombi, Marco; Dazert, Eva; Hindupur, Sravanth K.; Roszik, Jason; Moes, Suzette; Jenoe, Paul; Heim, Markus H.; Riezman, Isabelle; Riezman, Howard; Hall, Michael N.

doi:10.1016/j.ccell.2017.11.011

Cited by 310 publications

(280 citation statements)

References 68 publications

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“…These two lipid classes have been shown to be co‐regulated also under other disease states such as metabolic disorder due to high‐fat diet induced obesity in mice, in Alzheimer's disease, in the sphingolipidosis, Gaucher disease, and in cancer . In some of these cases, defects in intracellular transport were shown to be correlated with changes in ether lipids and sphingolipids (see below).…”

Section: Crosstalk Of Ether Lipids With Other Lipid Classesmentioning

confidence: 99%

On the road to unraveling the molecular functions of ether lipids

Jiménez‐Rojo

Riezman

2019

FEBS Letters

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Ether lipids are glycerolipids further classified into alkyl‐ether and alkenyl‐ether (also termed plasmalogens) lipids. The two ether lipid subclasses share the first steps of their synthesis. However, alkyl‐ether and alkenyl‐ether lipids differ in their structure and physico‐chemical properties (featuring different head groups) and, thus, probably in their functions. Ether lipids have intermittent distribution across the evolutionary tree and defects in their synthesis have been shown to perturb cellular homeostasis and lead to disease in humans. Here, we review their structure, their interactions with other lipids, and their potential roles in cellular functions, such as membrane homeostasis and membrane trafficking. Moreover, we discuss still unclear aspects of these lipids such as their subcellular distribution, and the need to unravel their molecular functions as well as how novel tools to study lipid biology will help clarify these aspects.

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Section: Crosstalk Of Ether Lipids With Other Lipid Classesmentioning

confidence: 99%

On the road to unraveling the molecular functions of ether lipids

Jiménez‐Rojo

Riezman

2019

FEBS Letters

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“…Lipid concentrations were calculated relative to the corresponding internal standards and then normalized to the total phosphate content of each total lipid extract. Sterol analysis was done as previously described 61 .…”

Section: Lipidomic Analysismentioning

confidence: 99%

“…In the case of glycerophospholipid and sphingolipid analysis, total lipid extract was split in two and dried. One aliquot was used without further treatments for glycerophospholipid analysis and inorganic phosphate determination while the other underwent methylamine treatment and desalting via butanol extraction61 .Glycerophospholipid and sphingolipid analysis was performed following a worm adapted version of a previously published method62 . LC-MS or HPLC grade solvents were used and the samples were pipetted in a 96 well plate (final volume = 100 µl).…”

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confidence: 99%

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Castillo

Hannich

Kaech

et al. 2019

Preprint

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words)Hedgehog (Hh) signaling is essential during development and in organ physiology. In the canonical pathway, Hh binding to Patched (PTCH) relieves the inhibition of Smoothened (SMO). Yet, PTCH may also perform SMO-independent functions. While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe non-canonical PTCH function. Here, we show that PTC-3 is a cholesterol transporter. ptc-3(RNAi) leads to accumulation of intracellular cholesterol and defects in ER structure and lipid droplet formation. These phenotypes were accompanied by a reduction in acyl chain (FA) length and desaturation. ptc-3(RNAi)induced lethality, fat storage and ER morphology defects were rescued by reducing dietary cholesterol. We provide evidence that cholesterol accumulation modulates the function of nuclear hormone receptors such as of the PPARa homolog NHR-49 and NHR-181, and affects FA composition. Our data uncover a novel role for PTCH in organelle structure maintenance and fat metabolism.No clear SMO homolog is encoded in the genome. In addition, some of the other downstream targets of the canonical Hh signaling pathway are also missing. In fact, it was proposed that SMO and those components were specifically lost during evolution in nematodes 15,21-23 . For example, SUFU is not conserved and the homolog of the transcription factor Gli, TRA-1, is involved in sex determination and gonad development in males and hermaphrodites 24 . Therefore, C. elegans provides an excellent model to study non-canonical, SMO-independent Hh signaling pathways, in particular in somatic tissues. To dissect SMO-independent PTCH functions, we concentrated on PTC-3, which is expressed in somatic tissues, in particular in the hypodermis, glia and gut 20 . We found that reduction of PTC-3 levels causes the accumulation of intracellular cholesterol and reduction in poly unsaturated fatty acids (PUFAs). Moreover, the endoplasmic reticulum lost most of its reticulate tubular form and developed elaborate sheet structures in the intestine. This effect in turn strongly impaired lipid droplet biogenesis, resulting in the inability of the animal to store fat.Reduction of dietary cholesterol rescued fat storage defects, the ER morphology defects, and improved development and survival in ptc-3(RNAi) animals. Cholesterol levels influence nuclear hormone receptor activity such as of the PPARa homolog NHR-49, which is involved in the regulation of FA synthesis. Thus, our data demonstrate that PTCH also controls intracellular cholesterol levels in C. elegans.Moreover, we show that PTCH thereby impinges on FA metabolism, organellar structure and fat storage capacity.

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“…Rapamycin and everolimus treatment has also shown therapeutic benefit for DN in other models, including rats with STZ-induced diabetes [203,204,205,206,207]. Some caution is required, however, as mTORC1 activity appears to protect diabetic livers from steatosis [208], though active mTORC2 promotes steatosis through induction of fatty acid and lipid synthesis [209], hence any treatment with mTORC inhibitors in diabetic patients must include close monitoring of a number of biomarkers for liver and kidney function as well as glucose homeostasis.…”

Section: Ageing and Age-related Pathologies Amenable To Treatment mentioning

confidence: 99%

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Walters

Cox

2018

IJMS

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Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

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mTORC2 Promotes Tumorigenesis via Lipid Synthesis

Cited by 310 publications

References 68 publications

On the road to unraveling the molecular functions of ether lipids

On the road to unraveling the molecular functions of ether lipids

Patched regulates lipid homeostasis by controlling cellular cholesterol levels

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

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