Ashley KangFaculty Advisor: Andreas Stahl, PhD

School of Public HealthHonors ThesisMay 16, 2016

The Effect of Coenzyme Q (CoQ) on Beige Adipogenesis in a

Human Cell Model

WAT, BAT, Beige adipocytes• White adipose tissue (WAT)

– Large lipid droplet with few mitochondria– Major depository for energy in lipid form

• Brown adipose tissue (BAT)– Smaller lipid droplets, rich in mitochondria

• Expression of Uncoupling protein 1 (Ucp1)– Main source of energy expenditure via uncoupling of oxygen

consumption from ATP production• Dissipates chemical energy to generate heat

• Beige adipocytes– Clusters of Ucp1-expressing adipocytes (like BAT) with

thermogenic capacity that develop in WAT depots

Sell et al., 2004

Coenzyme Q (CoQ) • Necessary component of

mitochondrial electron transport chain– Electron carrier from complex I

and II to complex III

• Longer isoprenyl side chains equate to a more hydrophobic molecule

• CoQ plays important role in brown adipocyte function– Increasing CoQ levels exogenously could be therapeutically

beneficial for a variety of metabolic diseases

Statins

• Most effective drugs in reducing elevated low-density lipoprotein (LDL) cholesterol– Can be classified into two groups: hydrophilic and lipophilic

• Atorvastatin is lipophilic

• Statins and CoQ share same precursor– Some studies suggest statins reduce endogenous

production of cholesterol and CoQ

Research Questions Can a human beige adipocyte model be established by

driving preadipocytes to differentiate into more beige adipocytes?

Given that CoQ is prevalent in BAT and that it can regulate Ucp1 levels in BAT and that statins may inhibit CoQ, will statins reduce Ucp1 expression in BAT? Subsequently, if we exogenously supplement CoQ, can it

rescue CoQ levels?

Hypothesis: We hypothesize that statin dependent decrease in Ucp1 expression in human beige cells is caused by CoQ deficiency, and supplementation of CoQ can rescue this inhibitory effect.

Courtesy of Dr. Ching-Fang Chang, PhD

Can we establish a human beige model?

• Intralipid treatment = difficult to accurately measure CoQ levels

• CoQ supplementation only increases levels at DIF D10-14 (4CBA/Ator) and not at Day -3-0• Suggested a receptor-dependent

CoQ uptake in mature adipocytes

• IL - stimulate differentiation / inhibit Ucp1 expression by promoting adipogenesis

Problems Using Intralipid (IL) Carrier

Using Micelle as New Carrier System

Conclusion Demonstrated that Atorvastatin and 4-CBA consistently

inhibited CoQ levels and Ucp1 expression in beige adipocytes

However, CoQ levels were neither efficiently nor effectively supplemented Question of whether CoQ supplementation can rescue

inhibitory effect could not be answered since results were inconclusive

Further research is necessary – many therapeutic benefits of CoQ supplementation, especially in protecting heart against mitochondrial dysfunction (diabetic cardiomyopathy / statin-induced myopathy)

Acknowledgments

The Stahl Lab• Dr. Andreas Stahl, PhD• Dr. Ching-Fang Chang, PhD• Dr. Jiehan Li, PhD• Kevin Tharp• Michael Park• Brittney Bivins • Hyo Min Park• Lacey Andrews

PH195• Dr. Charlotte Smith, PhD• Dr. Maureen Lahiff, PhD