Hypoxia‐inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia‐inducible factor‐1

Abstract

Hypoxia-inducible protein 2 (HIG2) has been implicated in canonical Wnt signaling, both as target and activator. The potential link between hypoxia and an oncogenic signaling pathway might play a pivotal role in renal clear-cell carcinoma characterized by constitutive activation of hypoxia-inducible factors (HIFs), and hence prompted us to analyze HIG2 regulation and function in detail. HIG2 was up-regulated by hypoxia and HIF inducers in all cell types and mouse organs investigated and abundantly expressed in renal clear-cell carcinomas. Promoter analyses, gel shifts, and siRNA studies revealed that HIG2 is a direct and specific target of HIF-1, but not responsive to HIF-2. Surprisingly, HIG2 was not secreted, and HIG2 overexpression neither stimulated proliferation nor activated Wnt signaling. Instead, we show that HIG2 decorates the hemimembrane of lipid droplets, whose number and size increase on hypoxic inhibition of fatty acid β-oxidation, and colocalizes with the lipid droplet proteins adipophilin and TIP47. Normoxic overexpression of HIG2 was sufficient to increase neutral lipid deposition in HeLa cells and stimulated cytokine expression. HIG2 could be detected in atherosclerotic arteries and fatty liver disease, suggesting that this ubiquitously inducible HIF-1 target gene may play an important functional role in diseases associated with pathological lipid accumulation.

Hypoxia-induced mobilization of stored triglycerides in the euryoxic goby Gillichthys mirabilis

“…Overall, the emerging picture regarding hypoxia and lipid metabolism in fish is that lipolysis is relatively independent of the lipolysis-stimulating effects of hypoxia-induced catecholamine release (Van den Thillart et al, 2002). This is in contrast to the effects of hypoxia on mammals, where a frequent hallmark of hypoxia or ischemia is a rise in glycerol and free fatty acid levels because hypoxia stimulates lipolysis in some tissues (Yin et al, 2009) while at the same time fatty acids accumulate because the -oxidation of fatty acids is inhibited by the absence of oxygen (Gimm et al, 2010). Interestingly, recent evidence in Drosophila has implicated a role for lipid metabolism in adaptation to severe chronic hypoxia, and adapted flies were found to express elevated transcript levels of lipid genes including Brummer lipase, the fly ortholog of ATGL (Azad et al, 2009 Histological inspection of G. mirabilis liver indicated that a substantial portion of the liver volume is given over to stored triglyceride and externally their livers have a cream coloration, presumably due to the presence of lipid.…”

“…Nevertheless, the fish still faces the challenge of what to do with the released fatty acids. Under normoxic conditions, fatty acids are metabolized by -oxidation in the mitochondria, but this requires oxygen, which will be scarce during hypoxia, and all available data indicate that fatty-acid -oxidation is inhibited during cellular hypoxia (Gimm et al, 2010). Largely owing to their hydrophobic properties, fatty acids can exert harmful effects, causing cellular injury (Katz and Messineo, 1981;Wang, Y. et al, 2009), and cytotoxicity is reported in certain syndromes in which -oxidation is reduced.…”

Role of lipid droplet proteins in liver steatosis

“…In addition, recent reports have demonstrated the characteristics of novel LD proteins, other than Plin family. These include mouse fat-specific protein 27 (FSP27) and its closely related human homolog cell death-inducing DFF45-like effector C (CIDEC), and hypoxia-inducible protein 2 (HIG2) [16,36] . Fatty liver is characterized 6 possible for Plin1 to be involved in the process of lipid accumulation in the liver under certain pathological conditions in human as described below.…”

Molecular genetic diagnostics of clear cell renal cell carcinoma

“…В ряде работ было показано, что HIG2 является прямой мишенью HIF1 и принима-ет непосредственное участие в липидном обмене в условиях гипоксии при раке [8]. Повышенная экс-прессия HIG2 часто обнаруживается при светлокле-точном ПКР и коррелирует с плохим прогнозом у па-циентов [9].…”