Lipoprotein lipase modulates net secretory output of apolipoprotein B in vitro. A possible pathophysiologic explanation for familial combined hyperlipidemia.

Williams, Kevin Jon; Petrie, Karen E.; Brocia, R W; Swenson, T L

doi:10.1172/jci115434

Cited by 68 publications

(21 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This would be expected to result in an increase in the net secretion of apoB-containing lipoproteins (because of decreased re-uptake of newly secreted apoB-lipoproteins, as shown in vitro (40) and in vivo (41). Against this possibility is that blockade of the LDLR by heparin (42,43) did not alter the relative differences in the conditioned media apoB-100 content after incubation with MA and OA (data not shown).…”

Section: Downloaded Frommentioning

confidence: 76%

Myristic acid increases dense lipoprotein secretion by inhibiting apoB degradation and triglyceride recruitment

Kummrow

Hussain

Pan

et al. 2002

Journal of Lipid Research

View full text Add to dashboard Cite

Fatty acids of varying lengths and saturation differentially affect plasma apolipoprotein B-100 (apoB-100) levels. To identify mechanisms at the level of production, rat hepatoma cells, McA-RH7777, were incubated with [ 35 S]methionine and either fatty acid-BSA complexes or BSA alone. There were increases in labeled apoB-100 secretion with saturated fatty acids palmitic and myristic (MA) (153 ؎ 20% and 165 ؎ 11%, respectively, relative to BSA). Incubation with polyunsaturated docosahexaenoic acid (DHA) decreased secretion to 26 ؎ 2.0%, while monounsaturated oleic acid (OA) did not change it. In pulse-chase studies, MA treatment resulted in reduced apoB-100 degradation, in agreement with its promotion of secretion. In triglyceride (TG) studies, synthesis was stimulated equally by OA, MA, and DHA, but TG secretion was relatively decreased with MA and DHA. With OA, the majority of newly secreted apoB100-lipoproteins was d р 1.006, but with MA, they were much denser (1.063 Ͻ d). Furthermore, the relative recruitment of newly synthesized TG to lipoproteins was impaired with MA. We conclude that mechanisms for effects of specific dietary fatty acids on plasma lipoprotein levels may include changes in hepatic production. In turn, hepatic production may be regulated by specific fatty acids at the steps of apoB-100 degradation and the recruitment of nascent TG to lipoprotein particles. -Kummrow, E., M. M. Hussain, M. Pan, J. B. Marsh, and E. A. Fisher. Myristic acid increases dense lipoprotein secretion by inhibiting apoB degradation and triglyceride recruitment.

show abstract

Section: Downloaded Frommentioning

confidence: 76%

Myristic acid increases dense lipoprotein secretion by inhibiting apoB degradation and triglyceride recruitment

Kummrow

Hussain

Pan

et al. 2002

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…In support of re-uptake, animals lacking LDL receptors exhibit increased hepatic production of VLDL (17,73), consistent with our original findings in cell culture (15). Furthermore, increased expression of bridging molecules, leading to enhanced apoB reuptake via HSPGs, may account for some of the hypolipidemic effects of fibric acid derivatives in vivo (18,74).…”

Section: Discussionmentioning

confidence: 99%

The Triple Threat to Nascent Apolipoprotein B

Fisher¹,

Pan²,

Chen³

et al. 2001

Journal of Biological Chemistry

175

View full text Add to dashboard Cite

We previously showed that ⍀-3 fatty acids reduce secretion of apolipoprotein B (apoB) from cultured hepatocytes by stimulating post-translational degradation. In this report, we now characterize this process, particularly in regard to the two known processes that degrade newly synthesized apoB, endoplasmic reticulum (ER)-associated degradation and re-uptake from the cell surface. First, we found that ⍀-3-induced degradation preferentially reduces the secretion of large, assembled apoBlipoprotein particles, and apoB polypeptide length is not a determinant. Second, based on several experimental approaches, ER-associated degradation is not involved. Third, re-uptake, the only process known to destroy fully assembled nascent lipoproteins, was clearly active in primary hepatocytes, but ⍀-3-induced degradation of apoB continued even when re-uptake was blocked. Cell fractionation showed that ⍀-3 fatty acids induced a striking loss of apoB 100 from the Golgi, while sparing apoB 100 in the ER, indicating a post-ER process. To determine the signaling involved, we used wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, which blocked most, if not all, of the ⍀-3 fatty acid effect. Therefore, nascent apoB is subject to ER-associated degradation, re-uptake, and a third distinct degradative pathway that appears to target lipoproteins after considerable assembly and involves a post-ER compartment and PI3K signaling. Physiologic, pathophysiologic, and pharmacologic regulation of net apoB secretion may involve alterations in any of these three degradative steps.Apolipoprotein B (apoB), 1 the major protein of atherogenic lipoproteins, is synthesized primarily by hepatic and intestinal cells. Most studies have focused on apoB metabolism in the liver, given the greater contribution to the plasma apoB pool made by that organ and the availability of relatively convenient primary and transformed hepatic cell models. The apoB message level and translational rate in hepatic cells are largely constitutive, and so secretory control is achieved primarily through co-and post-translational degradation of the protein (e.g. see Refs. 2-4 for recent reviews). Two specific mechanisms for the destruction of newly synthesized apoB in hepatic cells have been characterized. The first is endoplasmic reticulum-associated degradation (ERAD). Newly synthesized apoB in the endoplasmic reticulum (ER) is initially complexed with small amounts of lipid that are thought to be shuttled by the microsomal triglyceride transfer protein (MTP) (5). During severe lipid deprivation (6, 7) or MTP deficiency (8, 9), this initial lipidation fails, and the apoB becomes ubiquitinylated, which targets it for degradation by proteasomes (10 -14).The second mechanism for degradation of newly synthesized apoB is the re-uptake pathway. Re-uptake can occur after fully assembled apoB-containing particles have been exported across the plasma membrane but before they have diffused away from the vicinity of the cell by traversing the unstirred water layer that is adjacent...

show abstract

“…Thus, it is unlikely that the measured plasma LPL mass directly contributes to catalyzing hydrolysis of triglycerides in TG-rich lipoproteins in the plasma. Several researchers have shown that this inactive protein may act as a ligand targeting lipoproteins for binding to cell surfaces and receptors [18].…”

Section: Biochemical Properties Of Pre-heparin Lplmentioning

confidence: 99%

“…From the last decade, however, several groups of researchers [12][13][14][15][16][17][18][19] have shown the clinical significance of measuring LPL protein mass in plasma or sera by an enzyme-linked immunosorbent assay (ELISA) without heparin injection (simply put as serum or plasma LPL mass). In earlier studies, researchers applied the measurement of plasma or serum LPL mass to detailed analysis and characterization of type 1 hyperlipidemia (HLP) [16,17].…”

Section: Introductionmentioning

confidence: 99%