The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice

Mensenkamp, Arjen R.; Luyn, Marja J. A. van; Havinga, Rick; Teusink, Bas; Waterman, Ian J.; Mann, Christopher; Elzinga, Baukje M.; Verkade, Henkjan J.; Zammit, Victor A.; Havekes, Louis M.; Shoulders, Carol C.; Kuipers, Folkert

doi:10.1016/j.jhep.2003.12.011

Cited by 42 publications

(39 citation statements)

References 46 publications

(55 reference statements)

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“…We also approximated values for l a-LNA-CoA in relation to changing plasma levels of unesterified a-LNA during tracer perfusion. More accurate secretion rates of DHA derived from plasma a-LNA might be determined using longer intravenous [1-14 C] a-LNA infusions or in long-term in situ or in vivo liver perfusion studies (48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Upregulated liver conversion of α-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet

Igarashi

DeMar²,

et al. 2007

Journal of Lipid Research

102

138

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We quantified incorporation rates of plasmaderived a-linolenic acid (a-LNA, 18:3n-3) into "stable" liver lipids and the conversion rate of a-LNA to docosahexaenoic acid (DHA, 22:6n-3) in male rats fed, after weaning, an n-3 PUFA-adequate diet (4.6% a-LNA, no DHA) or an n-3 PUFAdeficient diet (0.2% a-LNA, no DHA) for 15 weeks. Unanesthetized rats were infused intravenously with [1-14 C]a-LNA, and arterial plasma was sampled until the liver was microwaved at 5 min. Unlabeled a-LNA and DHA concentrations in arterial plasma and liver were reduced .90% by deprivation, whereas unlabeled arachidonic acid (20:4n-6) and docosapentaenoic acid (22:5n-6) concentrations were increased. Deprivation did not change a-LNA incorporation coefficients into stable liver lipids but increased synthesis-incorporation coefficients of DHA from a-LNA by 6.6-, 8.4-, and 2.3-fold in triacylglycerol, phospholipid, and cholesteryl ester, repectively. Assuming that synthesized-incorporated DHA even tually would be secreted within lipoproteins, calculated liver DHA secretion rates equaled 2.19 and 0.82 mmol/day in the n-3 PUFA-adequate and -deprived rats, respectively. These rates exceed the published rates of brain DHA consumption by 6-and 10-fold, respectively, and should be sufficient to maintain normal and reduced brain DHA concentrations, respectively, in the two dietary conditions.-

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Section: Discussionmentioning

confidence: 99%

Upregulated liver conversion of α-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet

Igarashi

DeMar²,

et al. 2007

Journal of Lipid Research

102

138

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“…It is a slow process compared with our 5 min infusion study period, because radiolabeled VLDLs appear in plasma of unanesthetized rats only 15-20 min after the liver has been exposed to radiolabeled fatty acids through the oral route (35). The actual secretion rate might be measured in longer term in situ liver perfusion or feeding experiments or in vitro (35)(36)(37)(38). In cultured hepatocytes, the fraction of triglyceride secreted ranges from 35% in the absence of insulin to 65% in the presence of insulin, with the remainder being recycled via biolysis (39,40).…”

Section: Discussionmentioning

confidence: 99%

Low liver conversion rate of α-linolenic to docosahexaenoic acid in awake rats on a high-docosahexaenoate-containing diet

Igarashi

Chang

et al. 2006

Journal of Lipid Research

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We quantified the rates of incorporation of alinolenic acid (a-LNA; 18:3n-3) into ''stable'' lipids (triacylglycerol, phospholipid, cholesteryl ester) and the rate of conversion of a-LNA to docosahexaenoic acid (DHA; 22: 6n-3) in the liver of awake male rats on a high-DHA-containing diet after a 5-min intravenous infusion of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]a-LNA. At 5 min, 72.7% of liver radioactivity (excluding unesterified fatty acid radioactivity) was in stable lipids, with the remainder in the aqueous compartment. Using our measured specific activity of liver a-LNA-CoA, in the form of the dilution coefficient l a-LNA-CoA , we calculated incorporation rates of unesterified a-LNA into liver triacylglycerol, phospholipid, and cholesteryl ester as 2,401, 749, and 9.6 nmol/s/g 3 10 24, respectively, corresponding to turnover rates of 3.2, 8.7, and 2.9%/min and half-lives of 8-24 min. A lower limit for the DHA synthesis rate from a-LNA equaled 15.8 nmol/s/g 3 10 24 (0.5% of the net incorporation rate). Thus, in rats on a high-DHA-containing diet, rates of b-oxidation and esterification of a-LNA into stable liver lipids are high, whereas its conversion to DHA is comparatively low and insufficient to supply significant DHA to the brain. High incorporation and turnover rates likely reflect a high secretion rate by liver of stable lipids within very low density lipoproteins. -Igarashi, M., K. Ma, L. Chang, J. M. Bell, S. I. Rapoport, and J. C. DeMar, Jr. Low liver conversion rate of a-linolenic to docosahexaenoic acid in awake rats on a high-docosahexaenoate-containing diet. J. Lipid Res. 2006Res. . 47: 1812Res. -1822 Supplementary key words incorporation . turnover . synthesis . pulse labeling . infusion . diet Docosahexaenoic acid (DHA; 22:6n-3) is a nutritionally essential PUFA that must be obtained directly through the diet or be synthesized from its dietary essential precursor, a-linolenic acid (a-LNA; 18:3n-3). Mammalian tissues can convert a-LNA to DHA through serial steps of desaturation and elongation with final peroxisomal chain shortening (1-3). Both D5 and D6 desaturases participate in this conversion, but the D6 desaturase is considered to be rate-limiting (1, 4). Human and rat D5 and D6 desaturases are expressed abundantly in brain, liver, and heart (5, 6).Controversy remains regarding the extent of DHA synthesis in brain from a-LNA, compared with its delivery by blood to brain as DHA synthesized from a-LNA in the liver. In immature rats, Scott and Bazan (7) concluded that the brain does not synthesize its own DHA to a significant extent but that DHA converted from a-LNA in the liver can contribute to brain DHA via the blood stream. In adult rats fed a high-DHA-containing diet [2.3% (w/w) of total fatty acid], we recently used an in vivo kinetic pulselabeling model that confirmed a low synthesis rate of DHA from a-LNA in brain (2), as proposed for immature rats (see above), and also showed that a-LNA was largely b-oxidized or esterified unchanged into brain phospholipid. We d...

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“…The core proteins of HCV inhibit MTP activity and VLDL secretion, which consequently leads to hepatic steatosis (17,18). Reduced VLDL secretion also causes hepatic steatosis in apoE knockout mice (28)(29)(30) and in the mice that are lacking normal apoE function (31). It has been reported that the inhibition of VLDL secretion by HCV core protein or a mutation of apoE causes apoE to accumulate in HCC tissues.…”

Section: Discussionmentioning

confidence: 99%

Protein level of apolipoprotein E increased in human hepatocellular carcinoma

Yokoyama

Kuramitsu²,

Takashima³

et al. 2006

Int J Oncol

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Abstract. Many reports suggest that hepatic steatosis leads to hepatocellular carcinoma (HCC), including hepatitis C virus or non-alcoholic steatohepatitis. Proteomic study of tumor tissues from HCC patients, focusing on apolipoprotein (apo) of apoA1, apoB100 and apoE, was performed by immunoblotting. Although the significant changes of apoA1 or apoB100 could not be shown statistically, the immunoblotting showed the increase in protein level of apoE in the tumor tissues of 88% of patients without increase of apoE gene expression and serum level. These results suggest the accumulation of apoE by impaired secretion. Moreover, immunoblot analysis on twodimensional electrophoresis showed a strong possibility that sialylated forms of apoE also were increased in tumorous tissues of HCC. ApoE level in tumorous tissues is frequently elevated and may be a good histological marker for HCC.

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The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice

Cited by 42 publications

References 46 publications

Upregulated liver conversion of α-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet

Upregulated liver conversion of α-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet

Low liver conversion rate of α-linolenic to docosahexaenoic acid in awake rats on a high-docosahexaenoate-containing diet

Protein level of apolipoprotein E increased in human hepatocellular carcinoma

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