Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents Volume 3, No. 3, 2003
Contents
The
Physiological and Pharmacological Regulation of Lipid Metabolism
Guest
Editor: Dr. Michael E. Pape
Sources of
Acetyl-CoA: Acetyl-CoA Synthetase 1 and 2 Pp. 207-210
Takahiro
Fujino, Yukio Ikeda, Timothy F. Osborne, Sadao Takahashi, Tokuo T. Yamamoto and
Juro Sakai
ATP-citrate Lyase: A Potential Target for
Hypolipidemic Intervention
Pp. 211-217
Pieter
H.E. Groot, Nigel J. Pearce and Andrew D. Gribble
Physiological and Pharmacological Regulation
of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Pp. 219-227
Gene
C. Ness
Targeting Acetyl-CoA Carboxylase for
Anti-obesity Therapy Pp.
229-234
Grover
L. Waldrop and Jacqueline M. Stephens
Long-Chain-Fatty-Acid CoA Ligases: The Key to
Fatty Acid Activation, Formation of Xenobiotic Acyl-CoA Thioesters and
Lipophilic Xenobiotic Conjugates Pp. 235-244
Kathleen
M. Knights
Regulation of
Anne
Perez and Eric J. Niesor
New Approaches in the Management of Septic
Shock Pp. 251-259
L.
Bertolaccini , L. Barberis, F. Massaglia and E. Manno
Aromatase Inhibitors and Inactivators for the
Treatment of Postmenopausal Breast Cancer: A Review Pp. 261-276
Jurgen
Geisler
Abstracts
[Back to top] Sources of
Acetyl-CoA: Acetyl-CoA Synthetase 1 and 2
Takahiro
Fujino, Yukio Ikeda, Timothy F. Osborne, Sadao Takahashi, Tokuo T. Yamamoto and
Juro Sakai
Acetyl-CoA synthetase
(AceCS) catalyzes the production of acetyl-CoA from acetate, CoA and ATP. There
are two types of AceCS in mammals with different functions. One designated
AceCS1 is a cytosolic enzyme expressed in the liver and plays a role in the
production of acetyl-CoA for the synthesis of fatty acids and cholesterol. The
other enzyme AceCS2 is a mitochondrial matrix enzyme that produces acetyl-CoAs
mainly utilized for oxidation. Consistent with its function, the transcription
of AceCS1 is regulated by SREBPs. In contrast, the expression of AceCS2 is upregulated
during starvation and ketogenesis via unknown mechanisms. Specific inhibitors
of AceCS may provide therapeutic agents for the treatment of obesity,
cardiovascular diseases and type 2 diabetes.
[Back to top] ATP-citrate Lyase: A Potential Target for
Hypolipidemic Intervention
Pieter
H.E. Groot, Nigel J. Pearce and Andrew D. Gribble
Mammalian ATP-citrate
lyase (EC 4.1.3.8) is the main enzyme responsible for the supply of acetyl-CoA
for synthetic pathways. The enzyme is present in most tissues but particularly
in those with an active de novo synthesis of fatty acids like adipose tissue
and liver, especially during conditions of carbohydrate surplus. ATP-citrate
lyase is the only enzyme shared by the synthetic pathways of fatty acid and
cholesterol synthesis and due to this unique position, it has been proposed
that inhibition of this enzyme may be more efficacious in correcting (mixed)
hyperlipidemia than statins. In this manuscript we discuss the regulation of
(hepatic) fatty acid and cholesterol synthesis and review the data on the in
vitro and in vivo effects of inhibition of ATP-citrate lyase on lipid and
lipoprotein metabolism. We also review the literature on the identification of
inhibitors of ATP-citrate lyase. It is concluded that ATP-citrate lyase is a
target for hypolipidemic intervention but that a final evaluation requires the
identification of more potent inhibitors of this enzyme.
[Back to top] Physiological and Pharmacological Regulation
of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase
Gene
C. Ness
The conversion of
3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, catalyzed by
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), is considered to be the
ratelimiting step in the overall pathway of cholesterol biosynthesis. Although
expressed in virtually every tissue, HMGR is normally expressed at the highest
level in liver. Also the magnitude of regulation of HMGR in liver exceeds that
in any other tissue. Thus, this review focuses on regulation of hepatic HMGR.
Feedback regulation by the end product of the pathway, cholesterol, has been,
perhaps, the most extensively studied of the physiological and pharmacological
factors that act to regulate HMGR expression. This constitutes an important
homeostatic mechanism to maintain cholesterol levels within rather narrow
limits. A series of recent studies have now demonstrated that this regulation
occurs at the level of mRNA translation – not at the level of transcription as
has been widely accepted. The rapid stimulation of hepatic HMGR activity by
insulin is due to increased transcription rather than a change in
phosphorylation status. Glucagon opposes this effect. Insulin’s effect is
mediated through phosphorylation of
[Back to top] Targeting Acetyl-CoA Carboxylase for
Anti-obesity Therapy
Grover
L. Waldrop and Jacqueline M. Stephens
Acetyl-CoA carboxylase
catalyzes the first committed step in the synthesis of long-chain fatty acids.
ACC has three domains each having a different function in the conversion of
acetyl CoA to malonyl CoA. The activity of mammalian ACC is regulated by
allosteric effectors and by covalent modification, including phosphorylation
and dephosphorylation by various hormones. Also, the regulation of ACC by
phosphorylation is considered to be a target for hypolipidemic agents. There
are two mammalian isoforms of ACC and recent studies suggest that genetic or
pharmacological manipulation of both the mitochondrial isoform and cytosolic
isoforms of ACC may be effective antiobesity or anti-diabetic treatments. The
importance of ACC as an anti-obesity agent are supported by many studies which
demonstrate that modulation of fatty acid synthesis with an inhibitor of fatty
acid synthase can reduce food intake, increase fatty acid oxidation, and result
in rapid and profound weight loss. This review focuses on recent reports that
identify a new ACC inhibitor and suggest strategies for the development of new
ACC inhibitors. We also present evidence to suggest that inhibition of ACC in
non-adipose cells could be important and discuss recent studies which indicate
that modulation of ACC may be useful in the treatment of some types of cancer.
In summary, the pharmacological manipulation of acetyl-CoA carboxylase could be
a suitable target as an anti-obesity agent and current evidence also suggests
that inhibition of ACC could be a useful therapeutic for the treatment of both
diabetes and cancer.
[Back to top] Long-Chain-Fatty-Acid CoA Ligases: The Key to
Fatty Acid Activation, Formation of Xenobiotic Acyl-CoA Thioesters and
Lipophilic Xenobiotic Conjugates
Kathleen
M. Knights
Long-chain-fatty-aid
CoA ligases (EC 6.2.1.3) catalyse the bioactivation of fatty acids forming
acyl-CoA thioesters that are then substrates for anabolic and catabolic
pathways. In addition to these roles it is now recognised that fatty acyl-CoA
esters are key regulatory molecules affecting numerous cellular systems and
processes such as cell signalling, membrane fusion, protein acylation, protein
kinase C activity, and gene transcription as natural ligands of the peroxisome
proliferator-activated receptors. The key to both fatty acid activation and
xenobiotic acyl-CoA formation is the role played by the long-chain ligases
(LCL) that exist as a super family of membrane proteins. Focussing on
information relevant to humans, multiplicity of LCLs, their structural
features, and regulation are discussed. The fate of fatty acyl-CoAs and the
role of LCL in directing fatty acyl-CoA traffic are also considered as these
are integral to an appreciation of the consequences of xenobiotic-CoA
conjugation and the formation of lipophilic conjugates. Although fatty acid
activation is considered crucial to the provision of bioactive regulatory
molecules, xenobiotic-CoA conjugation is at times a barely recognised route of
drug metabolism. Knowledge of the consequences of xenobiotic-CoA formation and
the pervasive intracellular role these conjugates play can provide further
insight into xenobiotic metabolism and the interrelationship with lipid
metabolism.
[Back to top] Regulation of
Anne Perez and Eric J. Niesor
The nuclear receptors,
LXRs and FXR, are important regulators of lipid homeostasis. Among their
identified target genes is Apo E, which is a well-established plasma lipid
transport protein. This lipoprotein has been extensively studied and a wide
range of excellent reviews is available on it. Here, we reviewed the current
status of Apo E regulation by LXRs and FXR, although a handful of publications
are available on this topic. Functional response elements for LXRs and FXR have
been identified in the Apo E/C-I/C-IV/C-II gene cluster. The emerging picture
is that FXR regulates Apo E expression in the liver, whereas LXRs play a
similar role in extrahepatic tissues. We further investigated the regulation of
Apo E expression through LXR and FXR activation in liver- (HepG2), monocyte-
(THP-1) and colon- (Caco-2) derived cell lines. Apo E transcript levels are
increased in these three cell lines in response to LXR activation by the
specific agonist T0901317. Upon FXR stimulation by GW4064, Apo E mRNA levels
are increased in HepG2 and Caco-2, but not in the THP-1 cells, which do not
express FXR. Interestingly, in the liver-derived HepG2 and colon-derived Caco-2
cell lines, which both express LXRs and FXR, Apo E expression can be controlled
either by LXRs or FXR. In summary, these nuclear receptors display both
distinct and overlapping functions in lipid metabolism. Apo E can be regulated
by either LXRs or FXR, thus providing alternative mechanisms that control lipid
homeostasis in different tissues.
[Back to top] New Approaches in the Management of Septic
Shock
L. Bertolaccini , L. Barberis, F. Massaglia and E. Manno
In fact sepsis remains
a major cause of death in hospitalized patients. More than 750,000 cases of
severe sepsis occur annually in the
[Back to top] Aromatase Inhibitors and Inactivators for the
Treatment of Postmenopausal Breast Cancer: A Review
Jurgen Geisler
Breast cancer is often
an estrogen dependent disease and several endocrine treatment options are well
established in clinical practice. Although ovarian estrogen synthesis ceases at
menopause, estrogens may still be produced by the aromatization of androgens.
The “aromatase-pathway” is the major (and probably only) source of estrogens in
postmenopausal women. While the antiestrogen tamoxifen has dominated the field
of endocrine treatment of breast cancer for decades, novel aromatase inhibitors
and inactivators have recently challenged the position of tamoxifen.
Non-steroidal aromatase inhibitors like anastrozole and letrozole as well as
the aromatase inactivator exemestane have shown to have advantages compared to
the traditional drugs like tamoxifen and megestrol acetate. Currently, the
aromatase inhibitors and inactivators mentioned above are going to be
established as first-line treatment in postmenopausal women with
hormonesensitive, metastatic breast cancer. In addition, aromatase inhibitors
and inactivators have the potential to be used in the adjuvant setting as well
as in breast cancer prevention. This publication gives an overview about the
experience made with the most important aromatase inhibitors and inactivators
in all stages of hormone-dependent breast cancer focusing on the compounds
belonging to the so-called “third generation”: anastrozole, letrozole and
exemestane.