# Circadian Regulation of Lipoprotein Assembly

> **NIH NIH R01** · NYU WINTHROP HOSPITAL · 2020 · $345,600

## Abstract

Our long-term goal is to understand the molecular mechanisms pertaining to diurnal regulation of plasma lipid
levels and to determine how perturbations in this regulation contribute to dyslipidemia and atherosclerosis. We
observed that plasma triglyceride and cholesterol mainly associated with non-HDL apoB-lipoproteins exhibit
diurnal rhythms. We showed that plasma lipid diurnal rhythms are altered when animals are subjected to food
entrainment and are not seen in Clock mutant and Bmal1-/- mice. Our studies have revealed that both Clock
and Bmal1 (1) control diurnal regulation of MTP, an essential chaperone for the assembly of apoB-containing
triglyceride-rich lipoproteins, involving SHP; (2) regulate expression of ABCA1 via USF2 in macrophages and
control cholesterol efflux and atherosclerosis; and (3) regulate hepatic cholesterol excretion to bile by
modulating ABCG5/G8 expression via GATA4. We also observed that mice deficient in Clock or Bmal1 exhibit
sustained hyperlipidemia and are more susceptible to atherosclerosis. Hence, our overall postulate is that
circadian mechanisms protect against hyperlipidemia and atherosclerosis. This proposal pertains to circadian
regulation of fat mobilization that involves uptake of fatty acids, re-synthesis of triacylglycerols and lipoprotein
assembly by enterocytes and hepatocytes. Our first aim is to elucidate the role of Bmal1 in fatty acid uptake.
We will test the hypothesis that Bmal1 regulates CD36 expression via Rev-erbα to modulate fatty acid uptake.
Deregulation of this pathway increases fatty acid uptake by enterocytes and hepatocytes, thereby contributing
to steatosis and hyperlipidemias. Fatty acids taken up by enterocytes and hepatocytes are packaged into
lipoproteins involving two steps. We previously showed that the first step of primordial lipoprotein assembly is
regulated by Clock:Bmal1 by controlling MTP. Here, we hypothesize that Bmal1 also regulates the second
step lipoprotein core expansion by regulating the expression of Crebh and apoAIV. Therefore, the second aim
is to explain mechanisms by which Bmal1 regulates Crebh to modulate the assembly of large lipoproteins. We
postulate that Bmal1 regulates Crebh involving two mechanisms. First, Bmal1 upregulates Crebh and Rev-
erbα, when Rev-erbα levels increase it represses Crebh expression. At the end of the study, we expect to
demonstrate that Bmal1 controls lipid uptake and lipoprotein assembly and explain the molecular mechanisms
for this regulation. These studies will (1) elucidate key physiological, biochemical, and molecular mechanisms
regulated by Bmal1 that control fatty acid uptake and lipoprotein assembly; (2) show that lipid metabolism and
circadian regulatory mechanisms are intertwined; and (3) demonstrate that deregulation of circadian pathways
enhances hyperlipidemia, thereby increasing risk for atherosclerosis. These regulatory mechanisms might
have evolved to optimize fat absorption. The outcomes from these studies will impa...

## Key facts

- **NIH application ID:** 9986763
- **Project number:** 5R01DK121490-02
- **Recipient organization:** NYU WINTHROP HOSPITAL
- **Principal Investigator:** M Mahmood Hussain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,600
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986763

## Citation

> US National Institutes of Health, RePORTER application 9986763, Circadian Regulation of Lipoprotein Assembly (5R01DK121490-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986763. Licensed CC0.

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