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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Biotech Jim who wrote (18458)	4/2/1998 12:50:00 PM
From: David L. Hachey	Respond to of 32384

Jim, I don't know if either peptide affects TG levels. With regard to diabetes, and LGND's drugs, my working hypothesis is that the drug affects insulin sensitivity and/or signaling pathways in fat cells. This is roughly akin to the mysterious "Syndrome X" that has been around since the 1960s. This syndrome tries to relate the atherosclerosis that accompanies Type II diabetes with abnormal lipid metabolism. In this hypothesis, insulin has two primary actions on the adipocyte. First, increased insulin levels normally following a meal would downregulate TG lipolysis in adipose tissue and control the release of non-esterified fatty acids (NEFA) into plasma. This action is mediated via hormone sensitive lipase (HSL) in fat cells. The second action of insulin is to upregulate lipoprotein lipase (LPL) to remove TG from blood lipoproteins and thus store dietary fats in fat cells. If the signalling pathways are disrupted, NEFA output from adipocytes is NOT lowered during a meal and the excess NEFA is recycled through the liver where it is converted to very-low-density lipoprotein TG (VLDL-TG). In addition, because LPL activity is NOT properly upregulated, VLDL-TG (and other lipoprotein TGs) are not removed from plasma. The end result is elevated serum TG. The glitazones (i.e., troglitazone, piaglitazone), and probably other antidiabetic drugs, work to increase insulin sensitivity and restore the homeostatic regulation of serum lipids. The system is actually more complex than I describe, as it also involves modulation of beta-adrenergic receptors that are signalled by catecholamines to release NEFA, and which upregulate hormone sensitive lipase. The only other physiologic condition which acts in this manner is pregnancy. Pregnant women become insulin resistant, which results in elevated serum TG and cholesterol by the end of the 3rd trimester. The condition is often called the hyperlipidemia of pregnancy. It very quickly dissipates after pregnancy. The evolutionary purpose of this is to redirect maternal serum glucose and amino acids away from the mother to the developing fetus AND to convert the mother's energy metabolism to burning fatty acids instead of glucose and amino acids. Sorry for the biology lesson today, but it seemed relevant. Regards, ...Dave

To: Biotech Jim who wrote (18458)	4/2/1998 1:08:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

LGND just came out with another paper using mouse models to show that rexinoids such as Targretin actually lower triglyceride levels: Arterioscler Thromb Vasc Biol 1998 Feb;18(2):272-276 RXR agonists activate PPARalpha-inducible genes, lower triglycerides, and raise HDL levels in vivo. Mukherjee R, Strasser J, Jow L, Hoener P, Paterniti JR Jr, Heyman RA Department of Pharmacology, Ligand Pharmaceuticals, Inc, San Diego, Calif. 92121, USA. mukherjee@ligand.com Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are members of the intracellular receptor superfamily. PPARs bind to peroxisome proliferator-response elements (PPREs) as heterodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPARalpha activators and are used in the treatment of hyperlipidemia. We show that the RXR ligand LGD1069 (Targretin), like gemfibrozil, can activate the PPARalpha/RXR signal-transduction pathway, including transactivation of the bifunctional enzyme or acyl-CoA oxidase response elements in a cotransfection assay. The activation also occurs in vivo, whereby in rats treated with LGD1069 or gemfibrozil, bifunctional enzyme and acyl-CoA oxidase RNA are induced and the combination of LGD1069 and gemfibrozil leads to a greater induction. Importantly, in hypertriglyceridemic db/db mice treated with RXR or PPARalpha agonists, triglyceride levels are lowered, and the combination again has significantly greater efficacy. RXR agonists also raise HDL cholesterol levels without changing apoA-I RNA expression. This observation suggests the use of RXR-selective agonists, "rexinoids," either alone or in combination with a fibrate as a new therapeutic approach to treating patients with high triglyceride and low HDL cholesterol levels. PMID: 9484993, UI: 98143524