(P013) INTESTINAL ADAPTATION TO SHORT-TERM, EXTREME FAT CONSUMPTION ALTERS TRIGLCYERIDE-RICH LIPOPROTEIN SECRETION AND INTESTINAL LIPID HANDLING IN MALE AND FEMALE MICE

Background: Dysregulated postprandial metabolism including elevated chylomicron remnants, contributes to atherogenesis. The ketogenic diet is a patient-accessible metabolic health intervention whereby nutritional ketosis is achieved by consuming predominantly fat (>70% of kcal) with restricted carbohydrates and protein. It has been established that intestinal enterocytes package dietary triglycerides (TG) into chylomicrons for transport into circulation and store excess TGs as cytosolic lipid droplets (CLDs) such that nutrient absorption is maximized.

METHODS AND RESULTS: The current study aimed to characterize the impact of diet composition on postprandial intestinal lipid handling in male and female wild-type mice. We evaluated intestinal cytosolic lipid droplets, TG secretion rates, and intestinal morphology with short-term, high-fat Western diet (WD) and an extreme fat, low protein, carbohydrate-restricted ketogenic diet (KD) before developing obesity. For three weeks, mice previously fed a grain-based standard laboratory diet (GBD) were switched to a WD or KD. Both male and female KD-fed mice displayed significantly higher plasma TG levels in response to an olive oil gavage than WD- and GBD-fed mice. At fasting, intestinal TG mass was significantly higher in both male and female mice fed the KD than GBD- and WD-fed mice, providing increased substrate for chylomicron formation and secretion. Interestingly, KD feeding significantly enhanced intestinal-TG secretion rates in male but not female mice and KD-refeeding after a 12-hour fast led to significant jejunal TG accumulation in female mice compared to GBD- and WD-refeeding but not in male mice suggesting female mice. KD feeding lengthened the small intestine in male mice, whereas in female mice, jejunal villi length increased compared to GBD- and WD-fed mice.

Conclusion: Overall, KD feeding promotes functional changes to lipid mobilization and distinct morphological alterations to the small intestine compared to the WD diet over three weeks of feeding. Moreover, changes to intestinal lipid handling in response to KD feeding manifest differently in male and female mice. The contribution of elevated postprandial lipid secretion observed with a ketogenic diet on metabolic health and its impact on atherogenesis remains to be determined.