N-3 fatty acids stimulate intracellular degradation of apoprotein B in rat hepatocytes.

Wang, H; Chen, X; Fisher, Edward A.

doi:10.1172/jci116340

Cited by 130 publications

(105 citation statements)

References 44 publications

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“…In addition, the effect of PUFAs on total apoB48 recovery has been small in prior and the present studies (data not shown), owing to its under-representation in large lipid-rich particles (8,48). As indicated in Results, depending on the experiment, either the total amount of labeled apoB100 (intracellular plus secreted) or the separate recoveries from cells or conditional media were determined by immunoprecipitation followed by SDS/PAGE/fluorography/densitometry, as described in ref.…”

Section: Methodscontrasting

confidence: 60%

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Pan

Maitin

Parathath

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

119

108

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Hepatic secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins, is regulated through posttranslational degradation. We reported a degradation pathway, post-ER presecretory proteolysis (PERPP), that is increased by reactive oxygen species (ROS) generated within hepatocytes from dietary polyunsaturated fatty acids (PUFA). We now report the molecular processes by which PUFA-derived ROS regulate PERPP of apoB. ApoB exits the ER; undergoes limited oxidant-dependent aggregation; and then, upon exit from the Golgi, becomes extensively oxidized and converted into large aggregates. The aggregates slowly degrade by an autophagic process. None of the oxidized, aggregated material leaves cells, thereby preventing export of apoBlipoproteins containing potentially toxic lipid peroxides. In summary, apoB secretory control via PERPP/autophagosomes is likely a key component of normal and pathologic regulation of plasma apoB levels, as well as a means for remarkably late-stage quality control of a secreted protein.

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Section: Methodscontrasting

confidence: 60%

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Pan

Maitin

Parathath

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

119

108

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show abstract

“…Plasma and liver TAG concentrations were significantly lower in the CϩEX, KBR, and DF/KBRϩEX groups in comparison to the C group, data which are in agreement with reports that n-3 polyunsaturated fatty acid (PUFA) lowers plasma TAG concentration by decreasing hepatic TAG (45,46). Since most fish oils contain more EPA than DHA, EPA may contribute to reduced plasma TAG concentration (47).…”

Section: Discussionsupporting

confidence: 89%

Hypocholesterolemic Effects of Microbial Protease-Resistant Fraction of Katsuobushi in Ovariectomized Rats Depend on the Both Oil and Undigested Protein

Matsumoto

Erami

Ogawa

et al. 2007

J Nutr Sci Vitaminol

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“…Thus, apoB mRNA levels are relatively stable under many conditions, whereas secretion of apoB-containing lipoproteins is altered (1)(2)(3)(4)(5). The impact of this posttranslational regulation is demonstrated by the observations that only a small to moderate proportion of the newly synthesized apoB is eventually secreted from primary rat hepatocytes (6,7), McArdle cells (8), and HepG2 cells (9). A major portion of newly synthesized apoB undergoes rapid intracellular degradation in a pre-Golgi or ER compartment (10 -12) in HepG2 cells as well as in apoB cDNA-transfected Chinese hamster ovary cells (13).…”

Section: Apobmentioning

confidence: 99%

A Two-site Model for ApoB Degradation in HepG2 Cells

Sakata

Lele

et al. 1997

Journal of Biological Chemistry

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Newly synthesized apolipoprotein B (apoB) undergoes rapid degradation in a pre-Golgi compartment in HepG2 cells. A major site of this early degradation seems to be on the cytosolic side of the endoplasmic reticulum (ER) membrane and is sensitive to N-acetylleucinyl-leucinyl-norleucinal (ALLN), which can inhibit neutral cysteine proteases and/or proteasome activity. Oleate (OA) treatment, which facilitates translocation of nascent apoB across the ER membrane, also reduces early degradation. In the present studies, we have used brefeldin A (BFA), which inhibits vesicular transport from the ER to the Golgi, to demonstrate that apoB can also be degraded by an ER luminal proteolytic activity that is distinct from the ALLN-sensitive proteases. Thus, when BFA-treated HepG2 cells were cotreated with ALLN, which protects apoB but does not facilitate its translocation into the ER lumen, degradation of newly synthesized apoB was significantly reduced compared with cells incubated with BFA alone. However, apoB degradation was rapid and complete when OA was added to media containing either BFA or ALLN/BFA. These results suggested that OA, by increasing translocation of nascent apoB into the ER lumen, exposed apoB to an ALLN-resistant proteolytic pathway. When we incubated HepG2 cells with dithiothreitol (DTT)/OA/BFA or DTT/OA/ALLN/BFA, degradation of apoB was inhibited. Furthermore, addition of DTT resulted in the accumulation of a 70-kDa amino-terminal fragment of apoB. Both full-length and amino-terminal apoB were degraded if DTT was removed from the incubation media; both were secreted if only BFA was removed. Thus, even after apoB is translocated into the ER lumen (thereby avoiding the initial proteolytic pathway), it can potentially be degraded by a lumenal proteolytic process that is ALLN-resistant but DTT-sensitive. The present results, together with previous studies, suggest that at least two distinct steps may be involved in the posttranslational degradation of apoB: 1) the first occurs while apoB is partially translocated and is ALLNsensitive; and 2) the second occurs in the ER lumen and is DTT-sensitive. Finally, our results support the hypothesis that degradation of partially translocated apoB generates a 70-kDa amino-terminal fragment that is mainly degraded in the ER lumen by a DTT-sensitive pathway. ApoB1 secretion from cultured liver cells is regulated mainly at the posttranslational level. Thus, apoB mRNA levels are relatively stable under many conditions, whereas secretion of apoB-containing lipoproteins is altered (1-5). The impact of this posttranslational regulation is demonstrated by the observations that only a small to moderate proportion of the newly synthesized apoB is eventually secreted from primary rat hepatocytes (6, 7), McArdle cells (8), and HepG2 cells (9). A major portion of newly synthesized apoB undergoes rapid intracellular degradation in a pre-Golgi or ER compartment (10 -12) in HepG2 cells as well as in apoB cDNA-transfected Chinese hamster ovary cells (13). ApoB can be protected from e...

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N-3 fatty acids stimulate intracellular degradation of apoprotein B in rat hepatocytes.

Cited by 130 publications

References 44 publications

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Hypocholesterolemic Effects of Microbial Protease-Resistant Fraction of Katsuobushi in Ovariectomized Rats Depend on the Both Oil and Undigested Protein

A Two-site Model for ApoB Degradation in HepG2 Cells

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