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Lipid metabolism and lipophagy in cancer.

ABSTRACT: The tumor microenvironment can be hypoxic, acidic, and deficient in nutrients, thus causing the metabolism of tumor cells as well as the neighboring stromal cells to be remodelled to facilitate tumor survival, proliferation, and metastasis. Abnormal tumor lipid metabolism is a fairly new field, which has received attention in the past few years. Cross-talk between tumor cells and tumor-associated stromal cells modulates the high metabolic needs of the tumor. Fatty acid turnover is high in tumor cells to meet the energy as well as synthetic requirements of the growing tumor. Lipolysis of lipids stored in lipid droplets was earlier considered to be solely carried out by cytosolic lipases. However recent studies demonstrate that lipophagy (autophagic degradation of lipids by acidic lipases) serves as an alternate pathway for the degradation of lipid droplets. Involvement of lipophagy in lipid turnover makes it a crucial player in tumorigenesis and metastasis. In this review we discuss the metabolic reprogramming of tumor cells with special focus on lipid metabolism. We also address the lipid turnover machinery in the tumor cell, especially the lipophagic pathway. Finally, we integrate the current understanding of lipophagy with tumor lipid metabolism.

SUBMITTER: Maan M

PROVIDER: S-EPMC6086774 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Lipid metabolism and lipophagy in cancer.

Maan Meenu M Peters Jeffrey M JM Dutta Mainak M Patterson Andrew D AD

Biochemical and biophysical research communications 20180210 3

The tumor microenvironment can be hypoxic, acidic, and deficient in nutrients, thus causing the metabolism of tumor cells as well as the neighboring stromal cells to be remodelled to facilitate tumor survival, proliferation, and metastasis. Abnormal tumor lipid metabolism is a fairly new field, which has received attention in the past few years. Cross-talk between tumor cells and tumor-associated stromal cells modulates the high metabolic needs of the tumor. Fatty acid turnover is high in tumor ...[more]

PMID: 29438712

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Project description:Hypothalamic glial cells named tanycytes, which line the 3rd ventricle (3V), are components of the hypothalamic network that regulates a diverse array of metabolic functions for energy homeostasis. Herein, we report that TSPO (translocator protein), an outer mitochondrial protein, is highly enriched in tanycytes and regulates homeostatic responses to nutrient excess as a potential target for an effective intervention in obesity. Administration of a TSPO ligand, PK11195, into the 3V, and tanycyte-specific deletion of Tspo reduced food intake and elevated energy expenditure, leading to negative energy balance in a high-fat diet challenge. Ablation of tanycytic Tspo elicited AMPK-dependent lipophagy, breaking down lipid droplets into free fatty acids, thereby elevating ATP in a lipid stimulus. Our findings suggest that tanycytic TSPO affects systemic energy balance through macroautophagy/autophagy-regulated lipid metabolism, and highlight the physiological significance of TSPO in hypothalamic lipid sensing and bioenergetics in response to overnutrition.Abbreviations3V: 3rd ventricle; ACAC: acetyl-Coenzyme A carboxylase; AGRP: agouti related neuropeptide; AIF1/IBA1: allograft inflammatory factor 1; AMPK: AMP-activated protein kinase; ARC: arcuate nucleus; Atg: autophagy related; Bafilo: bafilomycin A1; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CNS: central nervous system; COX4I1: cytochrome c oxidase subunit 4I1; FFA: free fatty acid; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; ICV: intracerebroventricular; LAMP2: lysosomal-associated membrane protein 2; LD: lipid droplet; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MBH: mediobasal hypothalamus; ME: median eminence; MEF: mouse embryonic fibroblast; NCD: normal chow diet; NEFM/NFM: neurofilament medium; NPY: neuropeptide Y; OL: oleic acid; POMC: pro-opiomelanocortin-alpha; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; Rax: retina and anterior neural fold homeobox; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RER: respiratory exchange ratio; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TG: triglyceride; TSPO: translocator protein; ULK1: unc-51 like kinase 1; VCO2: carbon dioxide production; VMH: ventromedial hypothalamus; VO2: oxygen consumption.

Project description:Background & aimsCurrently, only a few genetic variants explain the heritability of fatty liver disease. Quantitative trait loci (QTL) analysis of mouse strains has identified the susceptibility locus Ltg/NZO (liver triglycerides from New Zealand obese [NZO] alleles) on chromosome 18 as associating with increased hepatic triglycerides. Herein, we aimed to identify genomic variants responsible for this association.MethodsRecombinant congenic mice carrying 5.3 Mbp of Ltg/NZO were fed a high-fat diet and characterized for liver fat. Bioinformatic analysis, mRNA profiles and electrophoretic mobility shift assays were performed to identify genes responsible for the Ltg/NZO phenotype. Candidate genes were manipulated in vivo by injecting specific microRNAs into C57BL/6 mice. Pulldown coupled with mass spectrometry-based proteomics and immunoprecipitation were performed to identify interaction partners of IFGGA2.ResultsThrough positional cloning, we identified 2 immunity-related GTPases (Ifgga2, Ifgga4) that prevent hepatic lipid storage. Expression of both murine genes and the human orthologue IRGM was significantly lower in fatty livers. Accordingly, liver-specific suppression of either Ifgga2 or Ifgga4 led to a 3-4-fold greater increase in hepatic fat content. In the liver of low-fat diet-fed mice, IFGGA2 localized to endosomes/lysosomes, while on a high-fat diet it associated with lipid droplets. Pulldown experiments and proteomics identified the lipase ATGL as a binding partner of IFGGA2 which was confirmed by co-immunoprecipitation. Both proteins partially co-localized with the autophagic marker LC3B. Ifgga2 suppression in hepatocytes reduced the amount of LC3B-II, whereas overexpression of Ifgga2 increased the association of LC3B with lipid droplets and decreased triglyceride storage.ConclusionIFGGA2 interacts with ATGL and protects against hepatic steatosis, most likely by enhancing the binding of LC3B to lipid droplets.Lay summaryThe genetic basis of non-alcoholic fatty liver disease remains incompletely defined. Herein, we identified members of the immunity-related GTPase family in mice and humans that act as regulators of hepatic fat accumulation, with links to autophagy. Overexpression of the gene Ifgga2 was shown to reduce hepatic lipid storage and could be a therapeutic target for the treatment of fatty liver disease.

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Lipid metabolism and lipophagy in cancer.

Publications

Lipid metabolism and lipophagy in cancer.

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