# The Role of DENND5B in Dietary Lipid Absorption

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $491,403

## Abstract

Project Summary
Postprandial plasma triacylglyceride levels are independently associated with risk of cardiovascular
disease. The intestine plays a key role in the regulation of dietary triacylglyceride absorption by
packaging and secreting lipids in chylomicron particles. The intracellular steps of chylomicron
biogenesis and transport have been fairly well described, however, there is a significant gap in our
understanding of the mechanism for the final steps of chylomicron secretion by enterocytes, specifically
post-Golgi transport and secretion. We recently identified a protein that plays a critical role in this
pathway, DENND5B. Our newly generated Dennd5b-/- mouse demonstrates an essential role for this
gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. Dennd5b-deficient mice
are resistant to diet-induced: obesity, changes in plasma lipids, and atherosclerosis. In humans, exome
sequencing studies reveal that a common DENND5B variant is correlated with body mass index. These
studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent
influence on body composition and peripheral lipoprotein metabolism. The overall objective of this
proposal is to gain fundamental knowledge about the process of dietary lipid absorption by the intestine
and to examine the impact of this process on systemic metabolic health. This objective aligns well with
the NIH mission to seek fundamental knowledge about living systems and to apply this knowledge to
enhance health. The Specific Aims of this proposal use our novel mouse model and in vitro
experiments to examine the mechanistic role of DENND5B in the intestine and its systemic metabolic
effects. Aim 1 will quantify the impact of Dennd5b on dietary lipid absorption and generate a
comprehensive spatial single-cell RNAsequencing data set for examination of gene networks that
participate in regulation of dietary lipid absorption. Aim 2 will examine the mechanism underlying
Dennd5b action in CM transport. Furthermore, this aim will use mass spectrometry and interactomics
analysis to expand our understanding of this process by identifying other interacting proteins which may
form a complex to facilitate chylomicron secretion by the intestine. Aim 3 will determine the impact of
Dennd5b on enterocyte metabolic function and peripheral lipid metabolism. Successful completion of
this proposal will fill a significant knowledge gap in the process of dietary lipid absorption. This work will
advance the field by providing mechanistic details for a key step in chylomicron secretion that can affect
systemic lipid homeostasis and metabolic health.

## Key facts

- **NIH application ID:** 10844647
- **Project number:** 5R01DK133184-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Scott M Gordon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $491,403
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844647

## Citation

> US National Institutes of Health, RePORTER application 10844647, The Role of DENND5B in Dietary Lipid Absorption (5R01DK133184-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10844647. Licensed CC0.

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