Hilpda Explained

Hypoxia inducible lipid droplet-associated (Hilpda, also known as C7orf68 and HIG-2) is a protein that in humans is encoded by the HILPDA gene.

Discovery

HILPDA was originally discovered in a screen to identify new genes that are activated by low oxygen pressure (hypoxia) in human cervical cancer cells.^[1] The protein consists of 63 amino acids in humans and 64 amino acids in mice.

Expression

HILPDA is produced by numerous cells and tissues, including cancer cells, immune cells, fat cells, and liver cells.^{[2] [3] [4] [5]} Low oxygen pressure (hypoxia), fatty acids, and beta-adrenergic agonists stimulate HILPDA expression.

Function

Nearly all cells have the ability to store excess energy as fat in special structures in the cell called lipid droplets. The formation and breakdown of lipid droplets is controlled by various enzymes and lipid droplet-associated proteins. One of the lipid droplet-associated proteins is HILPDA. HILPDA acts as a regulatory signal that blocks the breakdown of the fat stores in cells when the external fat supply is high or the availability of oxygen is low. In cells, HILPDA is located in the endoplasmic reticulum and around lipid droplets.^{[2] [4]} Gain and loss-of-function studies have shown that HILPDA promotes fat storage in cancer cells, macrophages and liver cells.^{[5] [3] [6] [7] [8]} This effect is at least partly achieved by suppressing triglyceride breakdown by inhibiting the enzyme adipose triglyceride lipase. The binding of HILPDA to adipose triglyceride lipase occurs via the conserved N-terminal portion of HILPDA, which is similar to a region in the G0S2 protein.^{[9] [7]}

Clinical significance

The deficiency of HILPDA in mice that are prone to develop atherosclerosis led to a reduction in atherosclerotic plaques, suggesting that HILPDA may be a potential therapeutic target for atherosclerosis.^[5] In addition, HILPDA may be targeted for the treatment of non-alcoholic fatty liver disease.

Notes and References

1. Denko N, Schindler C, Koong A, Laderoute K, Green C, Giaccia A . Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment . Clin Cancer Res . 6 . 21 . 480–7 . Feb 2000 . 10690527 .
2. Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Höning S, Eckardt KU, Warnecke C . Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1 . FASEB J . 24 . 11 . 4443–58 . Nov 2010. 20624928 . 10.1096/fj.10-159806 . free . 1309660 .
3. Mattijssen F, Georgiadi A, Andasarie T, Szalowska E, Zota A, Krones-Herzig A, Heier C, Ratman D, De Bosscher K, Qi L, Zechner R, Herzig S, Kersten S . Hypoxia-inducible lipid droplet-associated (HILPDA) is a novel peroxisome proliferator-activated receptor (PPAR) target involved in hepatic triglyceride secretion . J Biol Chem . 289 . 28 . 19279–93 . Jul 2014 . 24876382 . 10.1074/jbc.M114.570044 . 4094041 . free .
4. Dijk W, Mattijssen F, de la Rosa Rodriguez M, Loza Valdes A, Loft A, Mandrup S, Kalkhoven E, Qi L, Borst JW, Kersten S . Hypoxia-Inducible Lipid Droplet-Associated Is Not a Direct Physiological Regulator of Lipolysis in Adipose Tissue . Endocrinology . 158 . 35 . 1231–51 . May 2017 . 28323980 . 10.1210/en.2016-1809 . 5460841 . free .
5. Maier A, Wu H, Cordasic N, Oefner P, Dietel B, Thiele C, Weidemann A, Eckardt KU, Warnecke C . Hypoxia-inducible protein 2 Hig2/Hilpda mediates neutral lipid accumulation in macrophages and contributes to atherosclerosis in apolipoprotein E-deficient mice . FASEB J . 31 . 11 . 4971–84. Nov 2017 . 28323980 . 10.1096/fj.201700235R . 5460841 . free .
6. DiStefano MT, Danai LV, Roth Flach RJ, Chawla A, Pedersen DJ, Guilherme A, Czech MP . The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis . J Biol Chem . 290 . 24 . 15175–84 . Jun 2015 . 25922078 . 10.1074/jbc.M115.650184 . 4463459 . free .
7. Zhang X, Saarinen AM, Hitosugi T, Wang Z, Wang L, Ho TH, Liu J . Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia . eLife. 6 . e31132. Dec 2017. 29256392 . 10.7554/eLife.31132 . 5739538 . free .
8. VandeKopple MJ, Wu J, Auer EN, Giaccia AJ, Denko NC, Papandreou I . HILPDA Regulates Lipid Metabolism, Lipid Droplet Abundance, and Response to Microenvironmental Stress in Solid Tumors . Mol Cancer Res . 17 . 10 . 2089–101 . Oct 2019. 31308147 . 10.1158/1541-7786.MCR-18-1343 . 6774878 .
9. Padmanabha Das KM, Wechselberger L, Liziczai M, De la Rosa Rodriguez M, Grabner GF, Heier C, Viertlmayr R, Radler C, Lichtenegger J, Zimmermann R, Borst JW, Zechner R, Kersten S, Oberer M . Hypoxia-inducible lipid droplet-associated protein inhibits adipose triglyceride lipase . J Lipid Res. 59 . 3 . 531–541. Mar 2018. 29326160 . 10.1194/jlr.M082388 . 5832925 . free .