Cellular fatty acid uptake: a pathway under construction

Abstract

Membrane uptake of long-chain fatty acids (FAs) is the first step in cellular FA utilization and a point of metabolic regulation. CD36 facilitates a major fraction of FA uptake by key tissues. This review highlights the contribution of CD36 to pathophysiology in rodents and humans. Novel concepts regarding regulation of CD36-facilitated uptake are discussed (i.e. the role of membrane rafts and caveolae, CD36 recycling between intracellular depots and the membrane, and chemical modifications of the protein that impact its turnover and recruitment). Importantly, CD36 membrane levels and turnover are abnormal in diabetes, resulting in dysfunctional FA utilization. In addition, variants in the CD36 gene were shown recently to influence susceptibility for the metabolic syndrome, which greatly increases the risk of diabetes and heart disease.

Figure 1. Predicted topography of CD36 in the plasma membrane

(a) CD36 is a heavily glycosylated protein of 471 amino acids. Glysosylation accounts for the difference between the apparent (88Kd) and predicted (~53Kd) molecular weight of the protein. CD36 has a hairpin configuration in the plasma membrane. The extracellular domain has multiple N-linked glycosylation sites, a proline rich domain and a hydrophobic stretch that may associate with the membrane. The protein has two short cytoplasmic domains that are required for CD36 signaling after ligand binding. (b) Ubiquitination sites (in red) in the C-terminus and palmitoylation sites (in blue) in both the C- and N-tails are highlighted. The ubiquitination sites, which are sensitive to FA and insulin, may regulate CD36 sorting to the plasma membrane and CD36 turnover. Palmitoylation might help recruit CD36 to lipid rafts and could influence interaction with Src kinases. Regulation of CD36 palmitoylation is still unknown.

Figure 2. Ubiquitination and trafficking of CD36

This figure shows a proposed model for uniquitination-mediated CD36 trafficking. Ubiquitination is enhanced by FA and diminished by insulin. (i) Ubiquitinated or non-ubiquitinated CD36 is internalized into early/sorting endosomes, where the ubiquitinated form is selected and (ii) delivered to multivesicular body (MVB) and then to (iii) lysosomes for degradation. (iv) Non-ubiquitinated CD36 in early endosomes is recycled back to the plasma membrane. Deubiquitination of CD36 may be mediated by proteosome activity and is required for trafficking from early endosomes to MVB. This model is supported by the finding that treatment with MG132, a proteosomal inhibitor, leads to the accumulation of ubiquitinated CD36 [70].