Elevated systemic levels of
triglyceride-rich
lipoproteins (TRL) are a risk factor for the development of
atherosclerosis. In patients with
metabolic syndrome (MetS), intestinal TRL overproduction contributes to high systemic TRL levels, and recent studies suggest that systemic changes in MetS such as increases in plasma
fatty acids and
insulin resistance stimulate intestinal TRL production. The current study has examined whether increases in systemic TRL influence intestinal
lipid transport and
lipoprotein assembly pathways and evaluates the impact of these changes on the absorption and lymphatic transport of
lipids and a model lipophilic
drug (
halofantrine). Mesenteric lymph-duct or bile-duct cannulated rats were administered IV saline or (14)C-labeled
chylomicron (CM) (to increase systemic TRL) and intraduodenal (3)H
lipids and
drug. Changes to biliary
lipid output and lymphatic
lipid and
drug transport were subsequently examined. Increasing systemic TRL concentrations stimulated a significant increase in lymphatic
lipid and
drug transport. The increased
lipids in lymph were not derived from bile or the intestinal blood supply (
fatty acid or IV infused (14)C-CM). Rather, an increase in lymphatic transport of duodenally sourced
lipids was evident. Increasing plasma levels of TRL therefore stimulated
lipid absorption and lymphatic transport via a positive feedback process. The data also suggest that the changes to intestinal TRL formation that result from raised systemic TRL levels may impact on the absorption of highly lipophilic drugs and therefore the reproducibility of
drug treatments.