Hilpda, also known as hypoxia-inducible gene 2 (HIG2), is a hypoxia-inducible lipid droplet-associated protein. It acts as a selective inhibitor of intracellular lipolysis, mainly by inhibiting adipose triglyceride lipase. Hilpda is involved in regulating lipid droplet homeostasis, promoting lipid storage, and is associated with metabolic pathways related to lipid metabolism. Genetic models, such as gene knockout (KO) mouse models, have been crucial in studying its functions [2,4,5].

In a mouse model of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC), hepatocyte-specific Hilpda knockout (HilpdaΔHep) mice showed reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. This indicates that Hilpda plays a role in promoting NASH-driven HCC development, likely by restraining intracellular fatty acid flux in hypoxia [1]. In adipocytes, HILPDA-deficient mice under excessive fatty acid load had disrupted negative feedback regulation of lipolysis, leading to elevated lipotoxic stress, suggesting its importance in maintaining lipid homeostasis in adipocytes [3].

In conclusion, Hilpda is a key regulator of lipid metabolism, influencing lipid storage and lipolysis. The use of Hilpda KO mouse models has revealed its significance in diseases like NASH-driven HCC and in maintaining adipocyte lipid homeostasis, providing insights into the underlying mechanisms of these disease conditions and potential therapeutic targets.

References:

1. Povero, Davide, Chen, Yongbin, Johnson, Scott M, Razidlo, Gina L, Liu, Jun. 2023. HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia. In Journal of hepatology, 79, 378-393. doi:10.1016/j.jhep.2023.03.041. https://pubmed.ncbi.nlm.nih.gov/37061197/

2. de la Rosa Rodriguez, Montserrat A, Deng, Lei, Gemmink, Anne, Borst, Jan Willem, Kersten, Sander. 2021. Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes. In Molecular metabolism, 47, 101168. doi:10.1016/j.molmet.2021.101168. https://pubmed.ncbi.nlm.nih.gov/33465519/

3. Deng, Lei, Wu, Shuangcheng Alivia, Qi, Ling, Kersten, Sander. 2023. HILPDA is a lipotoxic marker in adipocytes that mediates the autocrine negative feedback regulation of triglyceride hydrolysis by fatty acids and alleviates cellular lipotoxic stress. In Molecular metabolism, 75, 101773. doi:10.1016/j.molmet.2023.101773. https://pubmed.ncbi.nlm.nih.gov/37422000/

4. Povero, Davide, Johnson, Scott M, Liu, Jun. 2020. Hypoxia, hypoxia-inducible gene 2 (HIG2)/HILPDA, and intracellular lipolysis in cancer. In Cancer letters, 493, 71-79. doi:10.1016/j.canlet.2020.06.013. https://pubmed.ncbi.nlm.nih.gov/32818550/

5. de la Rosa Rodriguez, Montserrat A, Kersten, Sander. 2020. Regulation of lipid droplet homeostasis by hypoxia inducible lipid droplet associated HILPDA. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1865, 158738. doi:10.1016/j.bbalip.2020.158738. https://pubmed.ncbi.nlm.nih.gov/32417386/