Download The role of sterol regulatory element binding proteins in regulating

Biochemical Society Transactions (2002) Volume 30, Part 6
B10 Yeast desaturases
Charles E. Martin, Chan-Seok Oh, Murali Vemula,
Pitchaimani Kandasamy, Ramesh Chellappa
Rutgers University, 604 Allison Road, Piscataway, NJ 08854
A I03
B12 Peroxisome proliferator activated receptors & the regulation
of mammalian fatty acid metabolism
S.A. Smith
GlaxoSrnithKline, Harlow, Essex, CM19 5AW, U K
The Saccharomyces O L E l gene encodes the intrinsic membranebound 6-9 fatty acid desaturase. O L E l expression is regulated at the
levels of transcription and mRNA stability by nutrient fatty acids
and molecular oxygen. Its transcription is controlled through two
distinct promoter elements, the FAR region, and a downstream
L O R E element that dramatically amplifies FAR-activated
expression under hypoxic or cobalt-stimulated growth conditions.
Transcription activation through both elements is repressed by
unsaturated fatty acids. The half-life of the O L E l mRNA is also
dramatically reduced upon exposure to unsaturated fatty acids.
O L E l expression is governed by two homologous membrane
bound proteins, Spt23p and Mga2p. These activate O L E l expression
through N-terminal polypeptides that are released from the
membrane through a ubiquitin-mediated mechanism that involves
processing by the 23s proteosome. Although proteolytic processing
of Spt23p can be repressed by polyunsaturated fatty acids, Mga2p
processing in normoxic cells appears to be regulated by a different
mechanism. Mga2p is essential, however, for the induction of the
high levels of expression that are triggered by hypoxia through the
LORE promoter element. Surprisingly, Mga2p also plays a critical
role in controlling O L E l mRNA stability, suggesting that there may
be a functional linkage between O L E l transcription and the
regulation of O L E l mRNA stability. (supported by N I H grant
GM45768).
Peroxisome proliferator activated receptors (WAR) are members of
the superfamily of ligand-activated nuclear transcription factors.
Three PPAR subtypes, PPARa, PPARG(P) and PPARy have been
described in mammals. The tissue distribution of PPARs is heterogeneous. PPARa is highly expressed in liver and skeletal muscle,
whilst PPARy is preferentially expressed in adipose tissues. In
contrast, PPARG is relatively abundantly expressed in most cell
types. Unlike most receptors, PPARs show low ligand specificity,
being activated by many long chain saturated and unsaturated fatty
acids, or by eicosanoids. PPARs are transcriptionally active as heterodimeric complexes with the retinoid receptor RXR and bind to
specific recognition sequences in the regulatory region of target
genes. Many PPAR-regulated genes encode proteins that regulate
fatty acid oxidation and storage. Elucidation of the biological
functions of PPARs has been aided by the development of PPARnull mice, the identification of humans bearing PPAR mutations,
together with the discovery of small molecule synthetic ligands that
selectively activate individual PPAR subtypes. Using these genetic
and pharmacological approaches it has been shown that PPARa predominantly regulates pathways of fatty acid oxidation, whereas
PPARy modifies fatty acid synthesis and storage in adipose tissues.
By reducing systemic fatty acid availability, thiazolidinedione
PPARy activators regulate glucose metabolism and are now used
clinically in the treatment of type 2 diabetes. In summary, PPARs
play a central role in the mechanisms that balance fatty acid
oxidation and storage in the face of fluctuations of dietary fat intake
and energy expenditure.
B11 Environmentally-induced regulation of acyl-CoA desaturase
813 The role of sterol regulatory element binding proteins in
genes
A.R. Cossins, P.A. Murray and A.Y. Gracey
School of Biological Sciences, University of Liverpool, Derby
Building, Brownlow Street, Liverpool L69 3GS
Cellular membranes act as sensitive detectors of environmental
change and they mediate a wide range of adaptive responses to
challenge. Prolonged cooling in cold-blooded organisms leads to
increased unsaturation of membrane lipids. This modifies membrane
physical structure and may enhance tolerance to increased cold and
improve performance at non-lethal temperatures. We have demonstrated in carp a substantial activity induction of the carp liver
A9-acyl C o A desaturase by transcriptional and post-translational
regulation. We have subsequently discovered a second carp hepatic
desaturase that is induced not by cold but by diet. The two differentially expressed genes appear to result from a recent genomic
duplication of the common carp. We have screened a variety of
other tissues for desaturase inductions using c D N A microarray
technology and find that cold-inducibility is not restricted to liver.
We arc also addressing the phenotypic significance of desaturase
induction by linking desaturase induction in the nematode worm, C.
elegans to induced cold tolerance. Indeed, we find that the 20-fold
cold-induction of fat-7 is related to an enhanced cold-tolerance,
supporting the widely-hypothesised causal link between the two.
regulating fatty acid synthesis
J.D. Horton
University of Texas Southwestern Medical Center, 5323 Harry
Hines Blvd., Dallas, TX 75390-9046
Sterol regulatory element-binding proteins (SREBPs) are a family of
membrane-bound transcription factors that regulate cholesterol and
fatty acid lipid biosynthesis. The three SREBP isoforms are
designated SREBP-la, SREBP-lc and SREBP-2. In vitro and in vivo
studies suggest that the SREBP-1 isoforms preferentially activate
genes involved in fatty acid synthesis, whereas SREBP-2 preferentially activates cholesterol biosynthetic genes. The predominate
SREBP-1 isoform expressed in most tissues is SREBP-lc. SREBP-lc
overexpression in liver selectively increases the m R N A levels of all
enzymes required for fatty acid biosynthesis, which results in a 6fold increase in fatty acid synthesis and hepatic triglyceride content.
Conversely, the genetic disruption of SREBP-lc through
homologous recombination results in a 50% reduction in fatty acid
biosynthetic enzyme mRNA levels and a 50% reduction in hepatic
fatty acid synthesis. O n e critical regulator of SREBP-lc expression
is insulin. In isolated hepatocytes, insulin treatment increases the
mRNA for SREBP-lc and its target genes. In vivo, SREBP-lc is
reduced in liver by fasting (low insulin) and elevated by refeeding
(high insulin). The mRNA levels of SREBP-lc target genes parallel
the changes in SREBP-lc expression in liver. Similarly, hepatic
SREBP-lc mRNA levels fall when rats are treated with streptozotocin (low insulin) and rise after insulin administration. Taken
together, the current evidence suggests that SREBP-lc is an
important transcriptional regulator of fatty acid synthesis and that
insulin’s lipogenic actions are mediated by SREBP-lc in liver.
0 2002 Biochemical Society