Nuclear receptor signaling in metabolic disease

PPARs and LXRs are central regulators of gene expression linked to lipid metabolism. We have provided in vivo evidence that the nuclear receptor signaling pathways have important roles in physiologic lipid homeostasis as well as in the pathobiology of atherosclerosis, dyslipidemia, and diabetes. This work has highlighted nuclear receptors as potential therapeutic targets for metabolic disease.

Beaven SW, Matveyenko A, Wroblewski K, Chao LC, Wilpitz D, Hsu TW, Lentz J, Drew B, Hevener A, Tontonoz P (2013) Reciprocal regulation of hepatic and adipose lipogenesis by LXRs in obesity and insulin resistance. Cell Metabolism 18:106–117.

Sallam T, Jones M, Gilliland T, Zhang Li, Wu X, Eskin A, Sandhu J, Casero D, Vallim T, Hong C, Katz M, Lee R, Whitelegge J, and Tontonoz P. (2016)­ Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature. 534:124-128.

Zhang L, Rajbhandari P, Priest C, Wu X, Vallim, T, Temel R, Sallam T, and Tontonoz P. (2017) Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP. eLife. 6:e28766.

Sallam T, Jones M, Thomas BJ, Wu X, Gilliland T, Qian K, Eskin A, Casero D, Zhang Z, Sandhu J, Salisbury D, Rajbhandari P, Civelek M, Hong C, Ito A, Liu X, Daniel B, Lusis AJ, Whitelegge J, Nagy L, Castrillo A, Smale S and Tontonoz P. (2018) Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nature Medicine. 24:304-312.


Membrane lipid homeostasis in physiology and disease

We are interested how the phospholipid and cholesterol composition of biological membranes impacts their function. Recent work has highlighted that phospholipid remodeling is used as a regulatory strategy to control biological processes such as lipoprotein production and cell proliferation. Furthermore, altered membrane composition affects inflammatory signaling pathways in macrophages and other immune cells.

Rong X, Albert CJ, Hong C, Duerr M, Chamberlain B, Tarling EJ, Ito A, Gao J, Edwards PA, Jung M, Ford DA, Tontonoz P (2013) LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metabolism 18:685–697.

Ito A, Hong C, Rong X, Tarling EJ, Hedde PN, Gratton E, Parks J, and Tontonoz P. (2015) LXRs repress inflammation through ABCA1-dependent regulation of membrane composition and TLR signaling. eLife. 4:e08009. (PMID 26173179)

Rong X, Wang B, Dunham M, Wong J, Young SG, Gratton E, Ford DA, Tontonoz P (2015) Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion. eLife 4:e06557.

Wang B, Rong X, Duerr MA, Hermanson D, Hedde PN, Wong T, Vallim T, Cravatt B, Gratton E, Ford DA, and Tontonoz, P. (2016) Intestinal phospholipid remodeling is required for dietary lipid uptake and survival on a high-fat diet. Cell Metabolism 23:492-504.


The intersection of immune and metabolic regulation

We have shown that nuclear receptors such as the LXRs and PPARs coordinate lipid metabolism and modulate immunity and inflammation. They also control the transcription of genes directly linked to lipid uptake, efflux, and transport and genes involved in inflammatory responses. Our studies have revealed mechanisms through which cholesterol and triglyceride metabolism affect immune responses.

Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P (2003) `y LXRs. Nat. Med. 9:213–219.

Joseph SB, Bradley MN, Castrillo A, Bruhn K, Mak PA, Pei L, Hogenesch J, O’Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P (2004) LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 19:299–309.

Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks J, Edwards PA, Jamieson BD, Tontonoz P (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111

Ito A, Hong C, Oka K, Salazar JV, Diehl C, Witztum JL, Diaz M, Castrillo A, Bensinger SV, Chan L, and Tontonoz P. (2016). Cholesterol accumulation in CD11c+ immune cells is a causal and targetable factor in autoimmune disease. Immunity. 45:1311-1326.


Lipid signaling in adipocyte development and function

Our group has a longstanding interest in adipocyte biology, stemming from the discovery of PPARg as the master adipocyte transcription factor. In recent years we have elucidated pathways underlying adipocyte differentiation and function, provided insight into how differential gene expression programs are established in white and brown adipose tissue. We have used high-throughput screening approaches to identify new genes and small molecules that modulate adipocyte development and function.

Villanueva CJ, Waki H, Godio C, Nielsen R, Chou W-L, Vargas L, Wroblewski K, Schmedt C, Boyadjian R, Mandrup S, Hevener A, Saez E, Tontonoz P (2011) TLE3 is a dual function transcriptional coregulator of adipogenesis. Cell Metabolism 13:413–27.

Villanueva CJ, Vernges L, Wang J, Drew B, Hong C, Tu Y, Hu Y, Peng X, Xu F, Saez E, Hevener AL, Reue K, Fong LG, Young SG, and Tontonoz P. (2013). Adipose subtype-selective recruitment of TLE3 or Prdm16 by PPARg specifies lipid storage versus thermogenic gene programs. Cell Metabolism. 47:423-45.

Wang J, Rajbhandari P, Damianov A, Waki H, Ham A, Sallam T, Villanueva CJ, Neilsen R, Mandrup S, Young SG, Reue K, Saez, E, Whitelegge J, Black DL, and Tontonoz P. (2017) RNA binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs. J. Clin. Invest. 127:987-1004.

Rajbhandari P, Thomas BJ, Feng A-C, Hong C, Wang J, Vergnes L, Sallam T, Wang B, Sandhu J, Seldin M, Lusis AJ, Fong LG, Katz M, Lee R, Young SG, Reue K, Smale ST, and Tontonoz P. (2018) IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172:218-233. [PMC5766418]


Regulation and function of lipoprotein receptor pathways

We have defined the E3 ubiquitin ligase IDOL as an LXR-dependent mechanism for feedback regulation of the LDLR pathway by sterols. We elucidated the structural basis for the IDOL–LDLR interaction and cellular pathways involved in LDLR degradation. We also defined the contribution of the LXR-LDLR pathway in controlling sterol homeostasis in mice and primates and uncovered links to central nervous system biology. IDOL is a major regulator of LDLR expression in the brain and a major determinant of susceptibility to Alzheimer’s-like disease in mice. Recent work has shown that control of brain ApoER2 levels by IDOL is critical for synaptic plasticity and learning and memory in mice.

Zelcer N, Hong C, Boyadjian R, Tontonoz P (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325:100–104.

Calkin AC, Goult BT, Zhang L, Fairall L, Hong C, Schwabe JWR, Tontonoz P. (2011) FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proc. Natl. Acad. Sci. USA 108:20107–112.

Hong C, Marshall S, McDaniel A, Boyadjian R, Tangirala R, Chamberlain B, Jung M, Fong LG, Young SG, Lee R, Temel R, Tontonoz P. (2014). The LXR-IDOL axis differentially regulates plasma LDL levels in monkeys and mice. Cell Metabolism 20:910–918.

Choi J, Gao J, Kim J, Hong C, Kim J, and Tontonoz P. (2015). The E3 ubiquitin ligase Idol controls brain LDLR levels, ApoE clearance and Aβ amyloidosis. Science Trans. Med. 314ra184.

Gao J, Marosi M, Choi J, Achiro JM, Kim S, Li S, Otis KO, Martin KC, Portera-Cailliau C, and Tontonoz P. (2017) The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. eLife 6:e29178.