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
Article: Niemann-Pick C1 like 1 protein is critical
for intestinal cholesterol absorption
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
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
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.
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
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
Where do you see your research leading in the
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
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
Department of Cardiovascular Endocrine Research
Kenilworth, NJ, USA