Cell and Developmental Biology University of Michigan

Research

Investigates the regulatory networks that control nutrient and energy metabolism, using integrated genomic, metabolomic, molecular, and mouse genetic tools. We are interested in exploring the pathogenic mechanisms underlying type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease, and their potential for therapeutic development.

Transcriptional coactivators in metabolic signaling
Transcriptional coactivators regulate chromatin states and are critical for the initiation and propagation of epigenetic signals. The PGC-1 family of coactivators serves as “hubs” that integrate nutrient and hormonal signals and regulates mitochondrial biogenesis, glucose and lipid metabolism. To define the molecular components of this regulatory network, we developed a genome-wide coactivation assay and interrogated over 1,700 human transcription factors and cofactors. These studies identified BAF60 family members as novel regulators of hepatic lipid metabolism and skeletal muscle fiber determination. Using proteomic tools, we investigated a hepatic PGC-1b transcriptional complex that controls plasma lipid homeostasis. We are currently investigating the mechanisms that regulate hepatic lipid homeostasis and the pathogenic events leading to fatty liver and its progression to non-alcoholic steatohepatitis (NASH).

Regulation of circadian metabolic rhythms
Organisms evolve diverse strategies to adapt their nutrient and energy metabolism to the light/dark cycles on the earth. While the temporal organization of metabolic activities is emerging as a fundamental aspect of energy homeostasis, how peripheral tissues integrate metabolic and timing cues still remains elusive. We previously discovered that PGC-1a integrates the biological clock with energy metabolism. PGC-1a receives input from the circadian pacemaker and regulates rhythmic expression of core clock and metabolic genes. More recently, we found that autophagy, a process critical for nutrient homeostasis, is highly rhythmic in vivo. Our research interests in this area are to define the regulatory networks that drive metabolic rhythms and to investigate how altered circadian metabolism contributes to metabolic disease.

Specification and reprogramming of tissue metabolism
The metabolic properties of adult tissues are highly specialized, yet they exhibit a notable degree of plasticity. For example, skeletal muscle fibers differ in their oxidative capacity and contractile function, whereas adipocytes from brown and white fats are not only different in fuel metabolism, but appear to have distinct developmental origins. In response to physiological and pathological stimuli, skeletal muscle and adipose tissues undergo extensive metabolic remodeling to meet their respective functional and energetic demands. Our laboratory is investigating the mechanisms that regulate the specification of myofiber and adipocyte energy metabolism, and exploring pathways for beneficial reprogramming of their metabolic properties.

Lab Members

• Fang Fang
  Research Fellow
• Carlos Hernandez
  Research Fellow
• Zhuoxian Meng
  Research Fellow
• Siming Li
  Assistant Research Scientist
• Lei Yu
  Research Lab Technician
• Di Ma
  Graduate Student
• Matthew Molusky
  Graduate Student
• Grace Wang
  Graduate Student

Publications

Representative Publications

1. Ma D, Panda S, Lin JD (2011) Temporal orchestration of circadian autophagy rhythm through C/EBPb. EMBO J. 30:4642-4651
2. Li S, Chen XW, Yu L, Saltiel AR, Lin JD (2011) Circadian metabolic regulation through crosstalk between casein kinase 1d and transcriptional coactivator PGC-1a. Mol. Endocrinol. (in press)
3. Hernandez C, Molusky M, Li Y, Li S, Lin JD (2010) Regulation of hepatic ApoC3 expression by PGC-1b mediates hypolipidemic effect of nicotinic acid. Cell Metabolism 12:411-419
4. Ma D, Li S, Lucas EK, Cowell RM, Lin JD (2010) Neuronal inactivation of PGC-1a protects mice from diet-induced obesity and leads to degenerative lesions. J. Biol. Chem. 285:39087-95
5. Li S, Arland E, Liu C, Vitvitsky V, Hernandez C, Banerjee R, Bottiglieri T, Lin JD (2009) Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1a. Am. J. Physiol. Endo. Metab. 296:E543-548
6. Li S, Liu C, Li N, Hao T, Han T, Hill DE, Vidal M, Lin JD (2008) Genome-wide coactivation analysis of PGC-1a identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metabolism, 8:105-117
7. Liu C, Li S, Liu T, Borjigin J, Lin JD (2007) Transcriptional coactivator PGC-1a integrates mammalian clock and energy metabolism. Nature, 447:477-481
8. Lin J, Yang R, Tarr PT, Wu P, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard CB, Spiegelman BM (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1b coactivation of SREBP. Cell 120:261-273
9. Lin J, Wu P, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jäger S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki A, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1a null mice. Cell 119:121-135
10. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1a drives the formation of slow-twitch muscle fibres. Nature 418: 797-801

List of publications in PubMed