Branched chain fatty acids (BCFAs) and CD36 : elucidating the molecular mechanisms of BCFA metabolism and the health impact of high-BCFA diet

Abstract

Understanding how dietary nutrients alter lipid metabolism in the host is important in deciphering the physiological mechanisms that regulate organismal health. Using the nematode Caenorhabditis elegans as a model organism, I found that a newly isolated gram-positive monomethyl branched-chain fatty acid (mmBCFA) rich bacteria, Microbacterium sp., isolated from C. elegans natural habitat can induce supersized lipid droplets (LDs) up to 30 µm in diameter in older animals and adversely affect their lifespan, development rate and brood size. Lipidomic analysis indicated that Microbacterium sp.-fed worms primarily accumulate dietary mmBCFAs in the triacylglycerides stored within LDs. Transcriptomic analysis discovered that the mmBCFA-rich bacteria diet would enhance fatty acid desaturase fat-7 expression and therefore polyunsaturated fatty acids (PUFAs) production to support LD biosynthesis and fusion processes. Additionally, the diet from Microbacterium sp. significantly inhibits creatine kinase argk-1, which results in the suppression of the AMP-activated protein kinase pathway, leading to a halt in mitochondrial beta-oxidation, enhanced lipid de novo synthesis and activation of a mitochondrial unfolded protein response (UPRmt) in C. elegans. Furthermore, using this enlarged LD-inducing bacteria diet, a gain-of-function missense mutation in scav-4 is identified to exacerbate the LD expansion phenotype while the loss of scav-4 results in diminished lipid storage in the worms. Lipidomic analysis showed that the L462F missense mutation nearly doubles the uptake of dietary mmBCFAs, whereas deletion mutants exhibit a reduced proportion of dietary mmBCFAs in total lipids. The localization of SCAV-4 on the intestinal apical membrane and its phylogenetic similarity to the human CD36 fatty acid transporter suggest that SCAV-4 is a homolog of CD36. Structural modelling indicates that the missense mutation is likely located within the transport tunnel, potentially affecting lipid transport. Among the six SCAV family members in C. elegans, SCAV-6 appears to be a less critical paralog compared to SCAV-4, sharing similar expression patterns and exhibit reduced lipid storage upon deletion. Notably, the transcriptomic analysis reveals that the SCAV-4 missense mutation does not cause much transcriptomic changes under the E. coli OP50 diet but affects over 3,000 genes in response to the Microbacterium sp. diet, suggesting that animals with SCAV-4(L462F) mutation are much more sensitive to the mmBCFAs-rich diet than the wild-type animals. This finding highlights the influence of host genetic variations in the interactions with dietary nutrients, which has a strong impact on host metabolism.