Regulation of hepatic lipoprotein biosynthesis by hormones
To identify key regulatory processes of hepatic lipoprotein production, we studied the effects of hormonal perturbations on lipoprotein biosynthesis in the rat. Insulin administration to cultured hepatocytes inhibits the secretion of triglycerides, and apolipoproteins B and E, but does not alter secretory rates of apoproteins A-I and C-III. Net synthesis of apoB and E is not reduced by the hormone, but the rate of transport of apoB from the endoplasmic reticulum to the Golgi is diminished, and the association of apoB with triglyceride declines, resulting in reduced formation of nascent VLDL. Thus, intracellular transport of individual apoproteins is a specific process that can be selectively regulated by physiologic stimuli and that can affect net hepatic lipoprotein production. Thyroid hormones enhance hepatic net production of apoA-I in the rat. Twenty minutes after injection of a receptor saturating dose of T3 into euthyroid rats, apoA-I gene transcription increases, reaches a maximum of 179% of control at 3.5 hours, and remains elevated for 48 hours. Levels of nuclear and cytoplasmic apoA-I mRNA increase at 1 hour and 2 hours, respectively, and exceed the levels expected from enhanced transcription more than twofold at 24 h. Daily administration of 35 ug T3/1OO g body weight s.c. for 1 week increases the abundance of nuclear and cytoplasmic apoA-I mRNA more than threefold, but reduces the transcription of the apoA-I gene to 42% of control injected animals. Thus, thyorid hormone rapidly stimulates apoA-I gene transcription, but posttranscriptional events enhancing the stability of nuclear apoA-I RNA contribute to the acute effect of T3 on apoA-I mRNA levels. In chronic hyperthyroidism, stabilization of nuclear apoA-I RNA precursors is the principal mechanism for enhanced apoA-I gene expression and may cause feedback inhibition of apoA-I gene transcription. Our studies also imply that in euthyroid rats the majority of nuclear apoA-I mRNA precursors is degraded.
KeywordsHepatocyte Culture mRNA Precursor Vesicular Stomatitis Viral Glycoprotein Albumin mRNA Hepatic Lipoprotein
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