Lipe, also known as hormone-sensitive lipase (HSL), is a key lipolytic enzyme. It plays a crucial role in lipid metabolism, especially in the breakdown of triglycerides to release fatty acids. This process is involved in energy homeostasis and is associated with various metabolic pathways [1,2]. Genetic models, such as knockout mouse models, are valuable for studying Lipe's functions.

Reducing Lipe by crossing 3K mice (representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation) with Lipe null mice attenuated motor deficits in male Lipe+/- knockdown (LKD)-3K mice. Heterozygous Lipe reduction was associated with an improved α-synuclein T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. However, in female 3K-LKD mice, an increase in pS129+ and larger lipid droplets likely decreased the benefits seen in males. This study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and supports Lipe as a promising target in males [1]. Biallelic Lipe null variants in patients led to a multisystemic disease with features like lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Lipomatous tissue and patient adipose stem cells (ASCs) showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. Lipe-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction [2].

In conclusion, Lipe is essential for lipid metabolism and energy homeostasis. Studies using Lipe knockout mouse models have revealed its significance in Parkinson-like deficits and a LIPE-related lipodystrophic syndrome. These findings suggest that Lipe could be a potential therapeutic target for certain neurological and metabolic diseases.