Lipe-KO Mouse

Lipe, encoding hormone-sensitive lipase (HSL), is a key lipolytic enzyme. HSL is involved in adipose tissue lipolysis, which is mediated by cAMP-protein kinase A (PKA)-dependent intracellular signalling [3]. Lipolysis is crucial for energy metabolism, as it releases fatty acids from triglyceride stores in adipose tissue, affecting overall lipid metabolism and energy homeostasis.

Reducing Lipe in mutant α-synuclein mice by crossing with Lipe null mice attenuated motor deficits in male Lipe+/- knockdown mice. This was associated with an improved α-synuclein T:M ratio, and dopaminergic neurotransmitter levels and fiber densities, suggesting Lipe's role in Parkinson-like diseases [1]. Also, biallelic Lipe null variants in humans result in a multisystemic disease. The disease features include lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Lipe-mutated adipose stem cells display impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction [2].

In conclusion, Lipe plays a vital role in lipid metabolism, adipocyte differentiation, and insulin response. Gene-knockout mouse models have been instrumental in revealing its functions in Parkinson-like deficits and a lipodystrophic syndrome. These findings contribute to understanding the underlying mechanisms of related diseases and may provide potential therapeutic targets.

References:

1. Adom, M A, Hahn, W N, McCaffery, T D, Fanning, S, Nuber, S. 2024. Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism. In Neurobiology of disease, 199, 106593. doi:10.1016/j.nbd.2024.106593. https://pubmed.ncbi.nlm.nih.gov/38971480/

2. Sollier, Camille, Capel, Emilie, Aguilhon, Caroline, Vigouroux, Corinne, Jéru, Isabelle. . LIPE-related lipodystrophic syndrome: clinical features and disease modeling using adipose stem cells. In European journal of endocrinology, 184, 155-168. doi:10.1530/EJE-20-1013. https://pubmed.ncbi.nlm.nih.gov/33112291/

3. Yu, Hwang Chan, Jeon, Yong Geun, Na, Ann-Yae, Bae, Eun Ju, Park, Byung-Hyun. 2024. p21-activated kinase 4 counteracts PKA-dependent lipolysis by phosphorylating FABP4 and HSL. In Nature metabolism, 6, 94-112. doi:10.1038/s42255-023-00957-x. https://pubmed.ncbi.nlm.nih.gov/38216738/