Rnf145, an E3 ubiquitin ligase, is crucial for maintaining cellular lipid homeostasis. It is involved in multiple pathways related to lipid metabolism, such as the regulation of membrane lipid composition and cholesterol biosynthesis [1,2]. Its function is significant as imbalances in these processes can lead to various diseases. Genetic models, like KO/CKO mouse models, can be valuable for studying its role in vivo.

In terms of membrane lipid regulation, Rnf145 senses membrane lipid composition. In unsaturated lipid membranes, it is stable and promotes the ubiquitination and degradation of the lipid hydrolase ADIPOR2. However, when membranes become enriched in saturated fatty acids, Rnf145 is auto-ubiquitinated and degraded, stabilizing ADIPOR2 to restore lipid homeostasis and prevent lipotoxicity [1].

Regarding cholesterol biosynthesis, Rnf145 expression is induced by LXR activation and high-cholesterol diet feeding. Transduction of Rnf145 into mouse liver inhibits cholesterol-related gene expression and reduces plasma cholesterol levels. Conversely, acute shRNA-mediated knockdown or chronic genetic deletion of Rnf145 potentiates cholesterol biosynthetic gene expression and increases cholesterol levels in liver and plasma. Mechanistically, Rnf145 triggers the ubiquitination of SCAP, potentially inhibiting its transport to the Golgi and subsequent processing of SREBP-2 [2]. Additionally, Rnf145, along with gp78 and Hrd1, mediates the sterol-induced degradation of HMG-CoA reductase, the rate-limiting enzyme of the cholesterol biosynthetic pathway. Knockdown of both Rnf145 and gp78 genes abrogates sterol-induced degradation of HMG-CoA reductase in CHO cells [3,4].

In conclusion, Rnf145 plays essential roles in regulating membrane lipid composition and cholesterol biosynthesis through its E3 ubiquitin ligase activity. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its significance in maintaining lipid homeostasis, which is relevant to diseases related to lipid metabolism disorders such as hypercholesterolemia [1,2,3,4].