Measuring Cholesterol: From Man to Yeast and Back 

Peter EspenshadeDepartment of Cell Biology

Cellular Control of Metabolism

Jürgen Berger/Max Planck Institute

Cells require tight regulation of metabolism to maintain homeostasis and viability.

Metabolism = the chemical reactions in a cell or organism

Homeostasis = control of a system keep it stable or constant

Hepatic ArteryHigh oxygen

Central VeinLow oxygen

Adapted from http://www.siumed.edu/

Cells Adapt to Their Environment to Maintain Homeostasis

 O2

Tumor Cells Adapt to Their Environment to Maintain

Homeostasis

Semenza, 2011

Semenza, 2008

Control of Cholesterol and Fat Synthesis

Acetyl-CoA, NADPH, O2, ATP

Cholesterol& Fat

Cholesterol& Fat

SynthesisSREBP

SREBP Controls Synthesis of Cholesterol and Fat

Korn et al., J. Clin. Invest. 1998, 102:2050-2060.

Normal Liver High SREBP

Loss of SREBP Prevents Diabetic Fatty Liver

Moon et al. 2012 Cell Metab. 15: 240-246.

Talk Outline

1. Yeast SREBP is controlled by oxygen

2. SREBP is required for virulence of pathogenic fungi.

3. What can this tell us about human cancer?

Conservation of SREBP in Fungi

SREBP Responds to Oxygen in Fungi

O2

Gene expression requiredfor low oxygen growth

SREBP

[ ]

Control of Cholesterol and Fat Synthesis

Acetyl-CoA, NADPH, O2, ATP

Cholesterol& Fat

Cholesterol& Fat

SynthesisSREBP

X

Conservation of SREBP in Fungi

Cryptococcus neoformans

Human opportunistic fungal pathogen

Infects ~30% of patients with AIDS in Africa and Southeast Asia

Common diseases: - meningoencephalitis - pneumonia

21%O2

14%

3%

Hypothesis: SREBP is required for growth in animals.

Cryptococcus neoformans

June Kwon-Chung – NIH, NIAID

SREBP is Required for C. neoformans Infection

7 days post-infection via tail vein

Conservation of SREBP in Fungi

SREBP is Required for A. fumigatus Low Oxygen Growth

Willger et al. PLoS Pathogens 2008

Wild-type

sre1D

SREBP is a Conserved Virulence Factor and Antifungal Drug

Target

Tumor Cells Adapt to the Environment to Maintain

Homeostasis

Semenza, 2011

Semenza, 2008

Is SREBP a Therapeutic Target for Pancreatic Cancer?

Tumor Hypoxia (Low O2)

Cholesterol & Fat Synthesis

Tumor Growth

SREBP

CRISPR Knockout of SREBP Pathway

Is the SREBP Pathway a Therapeutic Target for Pancreatic Cancer?

Tumor Hypoxia (low O2)

Cholesterol & Fat Synthesis

Tumor Growth

SREBP

Drugs

- Yeast SREBP is controlled by oxygen and required for fungal pathogenesis.

- SREBP may be required for pancreatic tumor growth and a new therapeutic target for this devastating disease.

- Studies of a simple yeast can provide important insights into human disease.

Summary

espenshadelab.com

FUNDINGAHN-JHU Cancer Research Fund

CURRENT LAB MEMBERSRisa BurrSara Clasen He GuJiwon HwangMeredith McGuireSumana Raychaudhuri, PhDWei Shao, PhDShan Zhao

COLLABORATORSC. neoformansJune Kwon-Chung – NIH

Pancreatic cancerAnirban Maitra – SKCCCZeshaan Rasheed – SKCCC