DHHC5 regulates intestinal lipid absorption and lymphatic function

The proper functioning of lacteals is essential for transporting chylomicrons, which play a crucial role in lipid absorption. Disruption of lacteal function is linked to a range of metabolic diseases, yet the regulatory mechanisms governing lacteal development and function have remained poorly understood.

A recent study published in Life Metabolism from Tong-Jin Zhao’s lab at Fudan University sheds new light on this crucial biological process. The team found that the palmitoyltransferase DHHC5 plays a pivotal role in maintaining the stability of the intestinal lymphatic system and regulating lipid absorption by controlling the localization of vascular endothelial growth factor receptor 2 (VEGFR2), a key factor in lymphatic endothelial cell function (Figure 1).

The study reveals that DHHC5 is essential for the proper function of lacteals. DHHC5 mediates the palmitoylation of CRYBG1, an actin-binding protein, thereby regulating the localization of VEGFR2 in lipid rafts of lymphatic endothelial cells (LECs). This process is crucial for the formation of “button-like” junctions between LECs that allow chylomicrons to enter lacteals.

Specifically, global deletion of the Dhhc5 gene (Dhhc5-IKO) in mice showed resistance to diet-induced obesity and exhibited impaired intestinal lipid absorption. Further analysis revealed significantly lower levels of triglycerides, free fatty acids, and chylomicrons in the plasma of Dhhc5-IKO mice, along with smaller chylomicron sizes. Notably, these mice also had higher triglyceride levels in their feces and exhibited longer small intestines, indicating disrupted lipid absorption.

By using tissue-specific knockout of Dhhc5 mice, the researchers further confirmed that DHHC5 regulates lipid absorption through regulating the localization of VEGFR2 in lipid rafts in LECs, thereby affecting VEGFR2 signaling. Furthermore, DHHC5 does not directly palmitoylate VEGFR2 or its co-receptor neuropilin-1. Instead, DHHC5 palmitoylates a newly identified substrate, CRYBG1, which in turn regulates VEGFR2’s interaction with lipid rafts. Knockdown of CRYBG1 led to increased ubiquitination and lysosomal degradation of VEGFR2, reducing its localization in lipid rafts and disrupting VEGF-A-induced signaling.

Taken together, this study uncovers the molecular mechanisms by which DHHC5 regulates intestinal lipid absorption and lymphatic function. The findings pave the way for new therapeutic strategies targeting lipid metabolism and lymphatic function.