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Plin4 is a lipid droplet protein (LDP) found predominantly in white adipose tissue (WAT). The Plin4 gene is immediately downstream of the Plin5 gene; the two genes exhibit distinct though overlapping tissue expression patterns. Plin4 is absent in brown adipose tissue (BAT) and liver and expressed at low levels in heart and skeletal muscle, whereas Plin5 is highly expressed in these oxidative tissues but at a low level in WAT. The physiological role of Plin4 remains unclear. We have generated Plin4 −/− mice by gene targeting. Loss of Plin4 has no effect on body weight or composition or on adipose mass or development. However, the triacylglycerol (TAG) content in heart, but not other oxidative tissues such as BAT, soleus muscle, and liver, is markedly reduced in Plin4 −/− mice. The heart of Plin4 −/− mice displays reduced Plin5 mRNA and protein levels (by ∼38 and 87%, respectively, vs. wild-type) but unchanged mRNA levels of other perilipin family genes (Plin2 and Plin3) or genes involved in glucose and lipid metabolism. Despite reduced cardiac TAG level, both young and aged Plin4 −/− mice maintain normal heart function as wild-type mice, as measured by echocardiography. Interestingly, Plin4 deficiency prevents the lipid accumulation in the heart that normally occurs after a prolonged (48-h) fast. It also protects the heart from cardiac steatosis induced by high-fat diet or when Plin4 −/− mice are bred into Lep −/− obese background. In conclusion, inactivation of Plin4 downregulates Plin5 and reduces cardiac lipid accumulation in mice.

Endothelial lipase (EL) is a determinant of high density lipoprotein-cholesterol (HDL-C) level, which is negatively correlated with atherosclerosis susceptibility. We found no difference in aortic atherosclerotic lesion areas between 26-week-old EL ؉ / ؉ apolipoprotein E-deficient (apoE ؊ / ؊ ) and EL ؊ / ؊ apoE ؊ / ؊ mice. To more firmly establish the role of EL in atherosclerosis, we extended our study to EL ؊ / ؊ and EL ؉ / ؉ low density lipoprotein receptor-deficient (LDLR ؊ / ؊ ) mice that were fed a Western diet. Morphometric analysis again revealed no difference in atherosclerosis lesion area between the two groups. Compared with EL ؉ / ؉ mice, we found increased HDL-C in EL ؊ / ؊ mice with apoE ؊ / ؊ or LDLR ؊ / ؊ background but no difference in macrophage content between lesions of EL ؊ / ؊ and EL ؉ / ؉ mice in apoE ؊ / ؊ or LDLR ؊ / ؊ background. EL inactivation had no effect on hepatic mRNAs of proteins involved in reverse cholesterol transport. A survey of lipid homeostasis in EL ؉ / ؉ and EL ؊ / ؊ macrophages revealed that oxidized LDL-induced ABCA1 was attenuated in EL ؊ / ؊ macrophages. This potentially proatherogenic change may have nullified any minor protective increase of HDL in EL ؊ / ؊ mice.Thus, although EL modulated lipoprotein profile in mice, there was no effect of EL inactivation on atherosclerosis development in two hyperlipidemic atherosclerosis-prone mouse models. -Ko, K. W. S., A. Paul, K. Ma, L. Li, and L. Chan. Endothelial lipase modulates HDL but has no effect on atherosclerosis development in apoE ؊ / ؊ and LDLR ؊ / ؊ mice. Endothelial lipase (EL; gene name LIPG ) is a recently described member of the triglyceride lipase gene family that shares considerable sequence homology with LPL and HL (1, 2). EL is synthesized by endothelial cells, where its expression is regulated by cytokines and physical forces (3, 4) as well as by cholesterol feeding (5). EL expression has also been demonstrated in macrophage cell lines (1, 2). Taken together and based on our knowledge of the functions of LPL and HL, these findings suggest potential regulatory roles for EL in lipoprotein metabolism, vascular biology, and atherosclerosis.LPL and HL have different degrees of both triglyceride lipase and phospholipase activities (6). The enzymatic activity of EL is distinct, it being mainly a phospholipase active toward all lipoprotein classes, although preferring HDL as a substrate (7). Accordingly, marked adenovirus-mediated overexpression of EL in low density lipoprotein receptor (LDLR) knockout mice reduced plasma VLDL and LDLcholesterol by ‫ف‬ 50% while almost reducing high density lipoprotein-cholesterol (HDL-C) to zero (2). Inactivation of EL through gene targeting (8, 9) or functional inhibition by antibody infusion (10) demonstrated that EL can indeed function as a key physiological regulator of HDL level, although details of its role in the catabolism of apolipoprotein B-containing lipoproteins have also expanded (11).A difference in the tissue specificity of EL (secreted by vascular en...

This review focuses on neuroadaptation to nicotine. The first part of the paper delineates some possible general mechanisms subserving neuroadaptation to commonly abused drugs. The postulated role of the mesocorticolimbic neuroanatomical pathway and drug-receptor desensitization mechanisms in the establishment of tolerance to, dependence on, and withdrawal from psychoactive drugs are discussed. The second part of the review deals with the pharmacological effects of nicotine at both pre- and postsynaptic locations within the central nervous system, and the still-perplexing upregulation of brain nicotine-binding sites seen after chronic nicotine administration. A special emphasis has been put on desensitization of presynaptic cholinergic mechanisms, and postsynaptic neuronal nicotinic-receptor function and its modulation by endogenous substances. A comparison with the inactivation process occurring at peripheral nicotinic receptors is also included. Finally, a hypothesis on the possible connections between desensitization of central cholinergic mechanisms and neuroadaptation to nicotine is advanced. A brief comment on the necessity of fully understanding the effects of nicotine on the developing nervous system closes this work.