Differential expression of apolipoprotein E messenger RNA within the rat liver lobule determined by in situ hybridization

✍ Scribed by Mara Massimi; Steven R. Lear; David L. Williams; Albert L. Jones; Sandra K. Erickson

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 525 KB
• Volume: 29
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510290504

✦ Synopsis

Apolipoprotein (Apo) E plays a key role in the metabolism of lipoproteins. It also modulates immunoregulation, cell growth and differentiation and the response to nerve injury. The liver is a major site of ApoE synthesis. Most of the circulating ApoE is thought to be of hepatic origin with most synthesized in hepatocytes. We showed that total liver ApoE messenger RNA (mRNA) levels were greater in normal adult female rats than in male and that genderspecific patterns of liver ApoE mRNA expression were present by in situ hybridization. In the male liver, the signal was strongest in the portal area, decreasing toward the central vein with the weakest signal in pericentral hepatocytes, resulting in a hepatic lobular gradient of expression. In female liver, a strong periportal signal also was observed that decreased in Zone 2, similar to that in males, but which then increased in pericentral hepatocytes resulting in a bowl-like distribution in marked contrast with that of the male. The results suggest that ApoE mRNA level is regulated differentially in hepatocytes within the liver plate and that the regulation is gender-dependent. Further, the results suggest that in males, hepatocytes in the portal area are the major contributors of ApoE to the plasma and/or sinusoidal pool, whereas in females, both portal and central area hepatocytes play an equal role. (HEPATOLOGY 1999;29:1549-1555.)

Apolipoprotein E (ApoE) is a glycoprotein component of several plasma lipoproteins including very low density lipo-proteins (VLDL), chylomicron and VLDL remnants, ␤VLDL, and some subclasses of high density lipoproteins (HDL). ApoE functions as a recognition signal mediating the clearance of lipoproteins by the low density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP; ␣ 2macroglobulin receptor). 2,3 ApoE also can be involved in reverse cholesterol transport from peripheral tissues to the liver 4 and in the delivery of cholesterol to cells in the local environment. 2,4,5 ApoE-containing HDL can provide cholesterol for bile acid synthesis and secretion. 6 A secretionrecapture process for ApoE has been proposed in which ApoE secreted from a cell needing cholesterol binds to circulating lipoproteins, thereby enhancing their uptake. [7][8][9] In addition to its importance in plasma lipid transport, ApoE plays a role in the response to nerve damage, 10,11 mediation of immune responses and cell proliferation, 12,13 and in regulating ovarian androgen production. 14 ApoE also has been implicated in the development of Alzheimer' s disease. [15][16][17] Studies of ApoE gene knockout mice have shown its importance in protection against development of atherosclerosis 18,19 and in brain and nervous system function. 20,21 The liver is the major site of ApoE synthesis, although ApoE gene expression has been found in many peripheral tissues including adrenal, heart, lung, spleen, kidney, ovary, testis, skin, and brain. 4,5,22,23 In some peripheral tissues, only specific cells produce ApoE, and its production is tightly regulated. 10,[24][25][26][27] In the liver, hepatocytes produce most of the ApoE, although Kupffer cells 28 and lipocytes 29, 30 also can synthesize it. However, endothelial cells in the liver do not synthesize detectable ApoE. 28 Hepatocytes exist as subpopulations that show functional specialization dependent on their spatial localization within the liver lobule. The lobule or liver plate is a microcirculatory unit conventionally divided into three zones: periportal (Zone 1), midzone (Zone 2) and pericentral (Zone 3). Evidence for a broad degree of heterogeneity within the liver plate is accumulating for uptake, storage, release, and synthesis of a variety of biologically important compounds, enzymes, and proteins; thus, hepatocytes from different regions of the liver can differ in their enzyme content and subcellular structure, and can have different metabolic capacities (for reviews, see Jungermann and Katz, 31 Gumicio, 32 and Gebhardt 33 ). Although the reasons for liver heterogeneity and its physiological function are poorly understood, it appears to be an important and efficient mechanism of regulation and adaptation to different metabolic states.

Few plasma proteins of liver origin have been studied for zonation of their expression. It has been proposed that plasma protein synthesis will be more highly expressed in the periportal area in the liver because of the necessity to spatially