Gastrointestinal lipid-sensing pathways

Gastrointestinal lipid-sensing pathways comprise a sophisticated network of receptors, transporters, and enzymes located throughout the alimentary canal that detect dietary fats and initiate physiological responses. Key molecular components include G protein-coupled receptors such as FFAR1 (GPR40), FFAR4 (GPR120), and GPR119, as well as nuclear receptors like PPARs and FXR, and transporters such as CD36 and NPC1L1 [4, 9, 11]. These pathways play a critical role in energy homeostasis by triggering the release of satiety-inducing and insulinotropic hormones, including GLP-1, CCK, and PYY, in response to lipid ingestion [4, 8]. Dysregulation of these sensing mechanisms is strongly linked to metabolic disorders such as obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), as well as certain gastrointestinal malignancies [1, 2, 11]. Pharmacological targeting of these pathways involves agonists for lipid-sensing GPCRs to improve glycemic control and inhibitors of lipid absorption or processing to manage hyperlipidemia and obesity [4, 7, 16]. While promising, therapeutic development faces challenges such as gastrointestinal side effects and the need for high tissue specificity to avoid systemic toxicity [6, 16]. Overall, these pathways represent a major frontier in the treatment of metabolic syndrome and related chronic conditions [8, 13].

Other names

Gut lipid-sensing systemIntestinal nutrient-sensing pathwaysEnteric lipid-sensing machineryIntestinal fat-sensing pathways

Modulation of lipid-sensing GPCRs (GPR40, GPR119, GPR120) to trigger incretin secretion; activation of nuclear receptors (PPARs, FXR, LXR) to regulate metabolic gene transcription; inhibition of lipid transporters (NPC1L1, CD36) or processing enzymes (MTP, DGAT) to reduce systemic lipid load.