# Molecular Basis of Cholesterol Metabolism

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $4,287,119

## Abstract

This Program Project Grant (PPG) began 40 years ago when two of us (Brown and Goldstein)
delineated the LDL receptor pathway for control of cholesterol metabolism and showed how genetic defects in
the receptor produce Familial Hypercholesterolemia and atherosclerosis. Over the ensuing years, our goals
broadened and the number of investigators increased, but the focus of this PPG remains the same, namely,
that many diseases result from misregulation of metabolism and that understanding the molecular basis for
regulation of lipid metabolism will lead to prevention and therapy of common lipid-related disorders, including
atherosclerosis and the complications of diabetes.
 In recent years, our PPG team has continued to produce high quality and unexpected results
that have opened new fields of investigation, two of which include: 1) discovery of the SREBP pathway as
a master regulator of lipid synthesis and LDL clearance, with implications for diseases ranging from
atherosclerosis to fatty liver disease; 2) discovery of the LDL-lowering action of PCSK9 and how loss-of-function
mutations in PCSK9 produce life-long reductions in plasma LDL and almost complete protection against
coronary artery disease – a discovery that stimulated development of two FDA-approved anti-PCSK9
monoclonal antibodies for treatment of severe hypercholesterolemia. In addition to these discoveries, the team
supported by this PPG has generated more than 400 unique cDNA clones, monoclonal antibodies, mutant cell
lines, and genetically engineered mice, all of which are provided to the scientific community with “no strings
attached.”
 We now apply for a 5-year renewal (Years 41-45) to probe more deeply into the biochemistry and
physiology of several proteins whose regulatory actions are central to lipid metabolism and human disease –
SREBPs and their regulators, Scap and Insigs; HMG-CoA reductase and two of its regulators, UBIAD1 and
PPD1; ACCs (acetyl-CoA carboxylases), key enzymes in fatty acid synthesis; UBXD8, a regulator of
unsaturated fatty acids; and ANGPTL3 and ANGPTL8, two regulators of triglyceride clearance. We will explore
the regulatory actions of these proteins through integrated interdisciplinary approaches covering the whole
range of biology, including genes, mRNAs, cells, experimental animals, and human subjects. If the past predicts
the future, we will continue to make discoveries that have direct implications for human health.
C/PPG 2015 – Overall - Project Summary

## Key facts

- **NIH application ID:** 9940749
- **Project number:** 5P01HL020948-44
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JOSEPH L GOLDSTEIN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $4,287,119
- **Award type:** 5
- **Project period:** 1997-07-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940749

## Citation

> US National Institutes of Health, RePORTER application 9940749, Molecular Basis of Cholesterol Metabolism (5P01HL020948-44). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9940749. Licensed CC0.

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