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FAST MOVING FRONTS

Scott W. Altmann talks with ScienceWatch.com and answers a few questions about this month's Fast Moving Front in the field of Pharmacology & Toxicology. The author has also sent along images of their work.
Altmann Article: Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption
Authors: Altmann, SW, et al.
SCIENCE, 303 (5661): 1201-1204 FEB 20 2004
Addresses: Schering Plough Corp, Res Inst, Dept Cardiovasc Endocrine Res, 2015 Galloping Hill Rd, Kenilworth, NJ 07033 USA.
Schering Plough Corp, Res Inst, Dept Cardiovasc Endocrine Res, Kenilworth, NJ 07033 USA.
Schering Plough Corp, Res Inst, Dept Discovery Technol, Kenilworth, NJ 07033 USA.
(addresses may have been truncated)

Why do you think your paper is highly cited?

Following the pioneering work on cholesterol metabolism in the body by Rudolph Schoenheimer in the late 1920s, the mechanism of sterol absorption has been questioned and debated for over 75 years. In the last two decades, growing experimental evidence has advanced the protein-mediated process over the diffusion-based model. One of the most significant scientific discoveries in this field was the development by Schering-Plough Research Institute (SPRI) of ezetimibe, a small molecule capable of blocking intestinal sterol absorption.

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The effectiveness of this drug in the human population invigorated an SPRI team effort to identify the protein target of this small molecule and understand the cellular process it regulates. The result of this research, published in this article, brought to the attention of the scientific community the functional understanding of a novel and poorly characterized protein, Niemann-Pick C1 like-1 (NPC1L1).

Does it describe a new discovery, methodology, or synthesis of knowledge?

This publication describes the characterization of a long-sought protein involved in a highly studied metabolic process. In addition, this paper described the focused use of bioinformatics combined with a set of simple hypotheses to sift through a large list of potential protein targets and ultimately identify one protein that has been postulated to exist.

Would you summarize the significance of your paper in layman’s terms?

The identification and characterization of NPC1L1 has opened a new door to experimental research in the field of cholesterol metabolism. This critical bit of information helps explain the complex process of cholesterol absorption. Identifying NPC1L1 provided an additional piece of the puzzle which also directly led to elucidating the molecular mechanism of the cholesterol absorption inhibitor ezetimibe. This work offers a new means for investigating how the dietary cholesterol one consumes affects plasma low-density lipoprotein cholesterol (LDL-C) levels.

How did you become involved in this research and were any particular problems encountered along the way?

Since the discovery of the cholesterol absorption inhibitor ezetimibe, Schering-Plough has always made a dedicated effort to understand as much as they could about ezetimibe and how it works. The latest achievement of this scientific effort was brought about by applying a different perspective to a vexing scientific problem. Rather than utilizing ezetimibe as a tool to directly identify and isolate its protein target, which after many years proved unsuccessful, we chose a hypothesis-driven selection process based upon what we thought the protein target should look like. This approach was followed by the conventional drug-target interaction studies to confirm our supposition.

Where do you see your research leading in the future?

Cardiovascular disease remains the leading cause of morbidity and mortality in the industrialized world and epidemiological studies have shown that both LDL and high-density lipoproteins (HDL) levels have profound effects in this disease. Given the success of cholesterol synthesis inhibitors (statins) and cholesterol absorption inhibitors (ezetimibe) for lowering LDL cholesterol levels in patients, it is imperative that we broaden our approach to treating this disease and find novel therapeutics to raise HDL. We anticipate working in this area for years to come.

Do you foresee any social or political implications for your research?

Impacting human health is definitely a social implication, and that’s ultimately the goal in continuing our research in this area.

With official government guidelines to lower LDL-C as advocated by the National Cholesterol Education Program (NCEP) and a population often incapable of meeting their cholesterol goals through diet and exercise alone, pharmaceutical intervention has become an important treatment solution. The area of cholesterol management has led to drug discoveries, including statins and ezetimibe, which have shown tremendous success in lowering LDL-C against the challenge of dietary excess.

As this research and other scientific understanding continue to push our ability to intervene on behalf of the population the social and political dialogue surrounding the work of the pharmaceutical industry will remain.

Scott W. Altmann, Ph.D.
Schering Plough Corporation
Research Institute
Department of Cardiovascular Endocrine Research
Kenilworth, NJ, USA



2008 : March 2008 - Fast Moving Fronts : Scott W. Altmann