Cellular differentiation and hormonal and dietary regulation of the stearoyl-CoA desaturase (SCD) genes
Our
laboratory is intersted in the molecular mechanisms of cellular
differentiation and gene expression. To address the problem, we are
studying a cell line of mouse fibroblasts (preadipocytes) that undergo
differentiation to adipocytes in cell culture. During the
differentiation process the levels of expression of a large number of
adipocyte-specific genes increase in a coordinate fashion. One of these
genes encodes stearoyl-CoA desaturase, an enzyme that catalyzes the de
novo biosynthesis of oleate and palmitoleate, which are the major
monounsaturated fatty acids found in triglycerides of fat cells. We are
using molecular biology approaches to characterize the mechanisms that
regulate the expression of the stearoyl-CoA desaturase gene (SCD); the
objective being to determine the molecular events which define the
differentiation process.
In addition to acting as a
marker of preadipocyte differentiation, the stearoyl-CoA desaturase
plays an important role in lipid metabolism and consequently we have
carried out studies aimed at defining the role of fatty acids,
cholesterol, carbohydrates, peroxisome proliferators, temperature and
hormones in the regulation of the stearoyl-CoA desaturase gene in
different tissues.
To address further the physiological
role of the SCD gene in lipid metabolism, we generated a mouse with a
targeted disruption of the SCD gene. This animal model has so far
enabled us to demonstrate that monounsaturated fatty acids the products
of SCD are required in the de novo biosynthesis of triglycerides,
phospholipids, cholesterol esters and wax esters.
Understanding
general cellular differentiation, has become an area of intense
research because of the far-reaching implications of lipid metabolism
and regulation on human diseases such as obesity, diabetes, cancer, and
heart disease. Fat deposition in obese individuals is aberrant in
comparison to non-obese individuals. This distinction is probably
genetic, and may involve overexpression of key enzymes such as SCD
and/or transcription factors. The ties between SCD expression,
adiposity and disease provide motivation to elucidate the mechanisms
involved in the control of this process. With the characterization and
understanding of the key regulatory genes involved in lipid metabolism,
manipulation of fat deposition and control of many metabolic disorders
may be possible.
We recently cloned the human homologue
of stearoyl-CoA desaturase gene. The availability of this gene will
enable us to study issues that affect human health.