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Fatty Acid Esters of Hydroxy Fatty Acids (FAHFA) Derivatives as Dual Modulators of Lipid Metabolism and Gut Microbiome in Obesity

ABSTRACT: Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs), endogenous lipids with anti-inflammatory and metabolic benefits, face challenges in clinical translation due to instability and high synthesis costs. This study introduces a scalable synthetic platform to engineer novel FAHFA derivatives with enhanced stability through bioisosteric modifications (e.g., amide, triazole bonds). Screening identified 12-TAASA and 12-HDTZSA as lead compounds, demonstrating potent inhibition of lipid uptake in hepatic cells without compromising glucose absorption. In a diet-induced obesity mouse model, oral administration of these derivatives reduced weight gain, improved glucose tolerance, and attenuated ectopic lipid deposition, rivaling the efficacy of semaglutide. Mechanistically, 12-TAASA and 12-HDTZSA remodeled the gut microbiome by enriching SCFA producing taxa. 12-TAASA also suppressed intestinal lipid absorption via transcriptomic regulation of key genes. These findings position synthetic FAHFAs as dual-action therapeutics, targeting both host lipid metabolism and gut microbiota dysbiosis, offering a promising strategy for obesity and metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE296368 | GEO | 2026/06/18

REPOSITORIES: GEO

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Project description:Preussin (Asperidine B) has recently shown its lipid-lowering effects by inhibiting intestinal absorption in human colorectal adenocarcinoma (Caco-2) cells and ex vivo intestinal loop in rats. While statins are widely prescribed as the primary line drug of choice for lowering hyperlipidemia, ezetimibe is the only drug that reduces intestinal cholesterol absorption, and is also optional for statin-nonresponsive individuals. To gain more understanding of the mechanisms of action and lead compounds, the derivatives of preussin: TP3, TP4, TP5, TP6, and TP7 have recently been synthesized, and the structures were confirmed using 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. However, whether these derivatives exhibited inhibitory effects on cholesterol absorption is unknown. Thus, this study aims to investigate the most potent inhibitory effect of cholesterol absorption of preussin derivatives using fluorescent-micelle cholesterol transport in intestinal Caco-2 cells, confirmed by an in vivo cholesterol absorption assay. Possible targets of the lead compounds were identified using a protein binding assay and label-free quantification using proteomic analyses. Results showed that all tested preussin derivatives markedly inhibited cholesterol absorption in the intestinal Caco2 cells to a similar extent to preussin and ezetimibe. TP5 (preussin B) consistently displayed a significant reduction of plasma cholesterol, identical to preussin and ezetimibe, with the same potency in rats. In addition, the proteomic analysis found that substantial differentially expressed changes in six proteins are involved in the lipid metabolism pathway. Interestingly, GOT2, as one of these six proteins in the lipid transport pathway, consistently interacts with TP5. The molecular docking and dynamic prediction showed that TP5 coupled with GOT2 at a pocket comparable to its cofactor. These findings suggest that preussin B has therapeutic potential as a candidate for a cholesterol absorption inhibitor to treat hyperlipidemia.

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Fatty Acid Esters of Hydroxy Fatty Acids (FAHFA) Derivatives as Dual Modulators of Lipid Metabolism and Gut Microbiome in Obesity

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