# Role of Multi-enzyme Complex in ApoBCL Secretion

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $516,600

## Abstract

Project 2. Role of Multi-Enzyme Complexes in ApoBCL Secretion
SUMMARY/ABSTRACT
Although statins and PCSK9 inhibitors decrease LDL-Cholesterol (LDL-C) levels and reduce cardiovascular
events, significant residual risk of CHD remains even in maximally treated individuals with low plasma levels of
LDL-C. Multiple lines of evidence support the contention that elevated plasma levels of triglyceride (TG)-rich
ApoB-Containing Lipoproteins (ApoBCLs) contribute significantly to this residual risk. Previously, we have
shown that the transcription factor, SREBP-1c, leads to activation of all genes encoding the enzymes involved
in FA synthesis. Excessive activation of SREBP-1c in liver results in high levels of FA and TG synthesis, VLDL
secretion, and ultimately hypertriglyceridemia. The studies in this project will characterize a new post-
translational regulatory mechanism that modulates FA and TG synthesis as well as VLDL production.
 The three enzymes that synthesize palmitate (C16:0) — ATP-citrate lyase (ACL), acetyl-CoA carboxylase
(ACC) and fatty acid synthase (FAS) — reside in the cytoplasm. The two enzymes that elongate and/or
desaturate palmitate, ELOVL6 and SCD1, are located in the ER, and the first enzyme in the synthesis of
glycerolipids, glycerol-3-phosphate acyltransferase 1 (GPAM), is located in the mitochondrial membrane. The
distinct subcellular locations of these enzymes produce a unique spatial challenge for the efficient synthesis of
FAs and TGs since the product of one enzyme is the substrate for the next.
 Our preliminary data suggest that the cytosolic FA synthesis enzymes form a complex. This discovery
stemmed from the characterization of a SREBP-1c-regulated gene designated MIG12. We found that MIG12
bound directly to ACCs, facilitated ACC polymerization, and increased overall rates of FA synthesis in liver.
MIG12 is structurally similar to another small protein designated S14. Our subsequent studies have shown that
S14 co-immunoprecipitated MIG12, ACC, and FAS suggesting that these proteins form a complex in the cytosol.
 Here, we will identify and characterize all proteins in the FA synthesis complex and determine how these
proteins associate with each other and with the ER and/or mitochondria. Next, we will determine whether the
formation and disassociation of the FA synthesis complex is regulated by hormonal signals in vitro and in vivo.
Finally, we will characterize the physiological function of lipogenic complex in vivo through a series of studies in
mice that lack the key proteins required for the formation of the FA synthesis complex. Combined, these studies
will provide important new insights into how the cytosolic lipogenic complex ultimately provides FAs to the ER
for further elongation and/or desaturation as well as to GPAM for TG synthesis and VLDL secretion.

## Key facts

- **NIH application ID:** 10755259
- **Project number:** 5P01HL160487-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JAY D. HORTON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $516,600
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755259

## Citation

> US National Institutes of Health, RePORTER application 10755259, Role of Multi-enzyme Complex in ApoBCL Secretion (5P01HL160487-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10755259. Licensed CC0.

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