# TTC39B in obesity and atherosclerosis

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $544,861

## Abstract

In human GWAS SNPs in the tetratricopeptide repeat domain protein 39B gene (TTC39B/T39)
that cause reduced hepatic expression are associated with increased HDL cholesterol. T39, a
scaffolding protein, promotes the ubiquitination and turnover of LXR. Western Type Diet (WTD)-
fed Ldlr-/-T39-/- mice showed decreased fatty liver, increased HDL, decreased LDL and reduced
atherosclerosis. T39 deficiency inhibited processing of sterol regulatory element binding protein
1 (SREBP-1) into its nuclear active form, due to an increase in microsomal phospholipids
containing polyunsaturated fatty acids (PUFA). We discovered that T39-/- macrophages also
show increased LXR., increased expression of genes mediating synthesis of PUFA, and
reduced inflammatory responses, suggesting a role of macrophages in reduced atherosclerosis
in mice with whole body T39 deficiency. Interestingly, treatment of WTD-fed Ldlr-/- mice with a
T39 antisense oligonucleotide (ASO) that decreased expression in both liver and adipose tissue
leads to reduced adiposity. While brown adipose tissue depots and food intake were
unchanged, T39 ASO treatment led to markedly increased expression of Ucp1 in WAT,
suggesting formation of beige adipocytes (beiging). We will investigate the role of T39 in
regulating LXR in macrophages and PPARγ in adipose tissue and effects on adiposity, insulin
resistance and atherosclerosis (Fig 1), linking to LXR studies in Proj 1, and of PPARγ studies in
Proj 3. Aim 1 will assess the impact of myeloid T39 deficiency on macrophage inflammation,
insulin resistance and atherosclerosis. We will explore the hypothesis that T39 deficiency
reduces ubiquitination and promotes stabilization of LXR in macrophages and thus enhances
LXR-mediated repression of inflammatory genes, primarily by increasing the synthesis of
phospholipids containing long chain PUFA. With Dr Tabas, we will determine if macrophage T39
deficiency promotes inflammation resolution.To determine if myeloid T39 deficiency is anti-
atherogenic, we will breed LysM-CreT39f/f mice in the Ldlr-/- background. Aim 2 will assess the
impact of adipocyte T39 deficiency on adiposity, insulin resistance and atherosclerosis. We will
breed AdipoQ-CreT39f/f mice in order to deplete T39 in WAT and assess adiposity, beiging and,
on the Ldlr-/- background, plasma lipoproteins and atherosclerosis. With Drs Accili and Qiang,
we will examine the impact of T39 deficiency on formation of beige adipocytes from the stromal-
vascular fraction (SVF). We will assess a specific hypothesis that T39 deficiency decreases the
binding of Rb family members to the E2F binding site in the promoter of Pparg1and other
beiging genes, promoting formation of beige adipocytes.

## Key facts

- **NIH application ID:** 10197190
- **Project number:** 5P01HL087123-14
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ALAN richard TALL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $544,861
- **Award type:** 5
- **Project period:** 2007-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197190

## Citation

> US National Institutes of Health, RePORTER application 10197190, TTC39B in obesity and atherosclerosis (5P01HL087123-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197190. Licensed CC0.

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