Fatty acid nitroalkenes regulate intestinal lipid absorption.

Fatty acid nitroalkenes (NO₂-FA) are tissue-protective and anti-inflammatory endogenous lipid mediators. A unique electrophilic character promotes reversible reactions with protein thiols, influencing key cellular functions. Given their generation during digestion and therapeutic potential, understanding the mechanisms and impact of NO₂-FA absorption and distribution is crucial. We investigated the intestinal absorption of orally administered 10-nitro-octadec-9-enoic acid (10-NO₂-OA) in male and female rats, using a portal vein- and mesenteric lymph duct-cannulated conscious model. There were no sex-related differences in the plasma distribution of 10-NO₂-OA and its inactive metabolite 10-nitro-octadecanoic acid (10-NO₂-SA). 10-NO₂-OA was extensively esterified into triglycerides at concentrations ∼60 times greater than the free acid. Duodenal administration showed that 10-NO₂-OA is primarily incorporated into chylomicron triglycerides (TAG) and transported via the lymphatic system, bypassing initial hepatic metabolism. Notably, 10-NO₂-OA significantly reduced lymph flow, chylomicron secretion, and impacted lymphatic TAG profile and transit. Assessment of intestinal TAG uptake by ³H-triolein tracing in mice showed that 10-NO₂-OA significantly reduced dietary fat absorption (∼75-50%), as evidenced by reduced radioactive levels in plasma w/o an endothelial lipase inhibitor. Quantitation of radioactivity distribution along the gastrointestinal tract showed a trend to greater lipid incorporation into the mucosa. Overall, these results show that NO₂-FA are primarily absorbed and transported through the lymphatic system as esterified TAG species, undergoing initial metabolism in enterocytes regardless of sex, with an unexpected impact on intestinal fatty acid uptake. These findings reveal novel actions of both endogenously-formed and orally-administered electrophilic NO₂-FA in modulating inflammatory and metabolic syndrome-related pathologies.