Dietary fat elevates hepatic apoA-I production by increasing the fraction of apolipoprotein A-I mRNA in the translating pool.
Elevated plasma high density lipoprotein cholesterol (HDL-C) levels are associated with a decreased risk for coronary heart disease. Ironically, diets enriched in saturated fat and cholesterol (HF/HC diets), which tend to accelerate atherosclerotic processes by increasing LDL cholesterol levels, also raise HDL-C. We have recently reported, using a human apoA-I (hapoA-1) transgenic mouse model, that the elevation of HDL-C by a HF/HC diet is attributable, in part, to an increase in the hepatic production of hapoA-1. To further define the hepatocellular processes associated with this induction, we have prepared primary hepatocytes from hapoA-1 transgenic mice. Rates of hapoA-1 secretion were 40% greater from cells prepared from animals fed the HF/HC relative to a low fat-low cholesterol (LF/LC) control diet. The abundance of hapoA-1 mRNA in these cells was similar between hepatocytes prepared from the HF/HC and LF/LC diet fed animals, suggesting a post-transcriptional mechanism that does not involve mRNA stability. Inhibition of secretion using brefeldin A revealed an increase in cellular hapoA-1 accumulation. Thus, the HF/HC diet apparently affects hepatic hapoA-1 production via a mechanism that is manifest prior to the exit of newly synthesized hapoA-1 from the Golgi. Pulse-chase experiments revealed a 39% greater peak hapoA-1 synthesis, with no difference in the degradation of total labeled hapoA-1 protein, as a result of the HF/HC diet feeding. Finally, resolution of liver S10 extracts via sucrose density sedimentation and metrizamide density equilibrium gradient centrifugation analyses both revealed similar increases (31 and 24%, respectively) in the relative percentage of hapoA-1 mRNA associated with the translating polysomal fractions as a result of the HF/HC feeding. Together, these data suggest that the HF/HC diet affects hepatic hapoA-1 production via a specific modulation in the relative amount of hapoA-1 mRNA in the polysomal pool. These observations provide an opportunity to explore a new mechanism regulating apoA-1 production and might lead to the development of novel therapies to elevate plasma HDL-C levels.
Azrolan
N
N
Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, New York 10021, USA.
Odaka
H
H
Breslow
J L
JL
Fisher
E A
EA
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics*; D001161:Arteriosclerosis / Q000209:etiology; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D008076:Cholesterol, HDL / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*
D016632:Apolipoprotein A-I; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D004041:Dietary Fats; D012333:RNA, Messenger