110: 259 -269, 2002). Heptanoate and C 5-ketone bodies derived from its partial oxidation in liver are precursors of anaplerotic propionyl-CoA in peripheral tissues. It was hypothesized that increasing anaplerosis in peripheral tissues would boost energy production. In the present study, we tested the potential of a triheptanoin emulsion as an intravenous nutrient. Normal rats were infused with triheptanoin intravenously or intraduodenally at up to 40% of caloric requirement. The blood concentration ratio (heptanoate/C 5-ketone bodies) was high with intravenous and low with intraduodenal triheptanoin infusion. During intravenous infusion of triheptanoin, lipolysis was stimulated but appeared compensated by fatty acid reesterification. During intraduodenal infusion of triheptanoin, lipolysis was not stimulated. Our data support the hypothesis that intravenous triheptanoin could be used to treat decompensated patients with long-chain fatty acid oxidation disorders.heptanoate; C 5-ketone bodies; fatty acid oxidation disorders; anaplerosis INHERITED FATTY ACID OXIDATION DISORDERS (FOD) include defects of the cell membrane carnitine transporter, the "carnitine cycle" (CPT I, translocase, CPT II), or the mitochondrial ␤-oxidation spiral. The most common disorders of ␤-oxidation affect very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, isolated long-chain hydroxyacylCoA dehydrogenase, and medium-and short-chain acyl-CoA dehydrogenase. Patients with long-chain FOD commonly present with recurrent hypoketotic hypoglycemia, hypertrophic or dilated cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, muscle weakness, and hypotonia, (for a review, see Ref. 21). There is considerable phenotypic variation associated with nearly all of these disorders.The classical chronic treatment of long-chain FOD involves frequent feeding with a diet adjusted so as to lower long-chain fat intake from the usual 30 -35% of total kilocalories to ϳ20%, including essential fatty acids. The decrease in energy from long-chain fats is partly compensated by an increase in carbohydrates, often with cornstarch at bed time. In addition, even carbon medium-chain triglycerides (trioctanoin/tridecanoin) are added to the diet. This is because fatty acids with 8 -10 carbons enter the mitochondrion as carboxylates, which, after activation, require only those ␤-oxidative enzymes with medium-and short-chain length specificity. The dietary treatment with medium-chain triglycerides is obviously restricted to long-chain disorders and is contraindicated for medium-and short-chain deficiencies.A new strategy was recently conceived for the dietary treatment of long-chain FOD, i.e., providing about one-third of the calories as triheptanoin (22). The catabolism of heptanoate yields anaplerotic propionyl-CoA in addition to acetyl-CoA. It was hypothesized that part of the energy deficit in FOD patients results from a decrease in the concentration of citric acid cycle intermediates in muscle and heart cells. These intermediates carry the carb...

Complement per se has been shown to play an important role in demyelinating disease but controversy remains regarding the role of C3 in the development and progression of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In this study we used C3 -/-mice to confirm previous findings that C3 is required for full development of EAE. Furthermore, C3 +/-mice (with serum C3 levels 50% that of wild type mice) developed EAE with a severity intermediate between wild type and C3 -/-mice. Importantly transfer of wild type encephalitogenic T cells to C3 -/-mice resulted in attenuated EAE. C3 -/-mice with EAE had fewer CD4 + and CD8 + T cells in the CNS and 50% fewer of these cells produced IFN-γ compared to wild type mice. When treated with anti-CD3 antibody, CD4 + T cell from wild type and C3 -/-mice had similar activation profiles as judged by IFN-γ production and CD25 and CD69 expression, indicating there is no gross or intrinsic defect in T cells from C3 -/-mice. T cells from primed C3 -/-mice proliferated comparably to that of control T cells on re-stimulation with MOG peptide. Our results confirm a requirement for C3 for maximal development of EAE and suggest that receptors for C3-derived activation fragments might be a viable therapeutic target for prevention and treatment demyelinating disease.

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We reported previously that a substantial fraction of the acetyl groups used to synthesize malonyl-CoA in rat heart is derived from peroxisomal β-oxidation of long-chain and very-long-chain fatty acids. This conclusion was based on the interpretation of the 13 Clabelling ratio (malonyl-CoA)/(acetyl moiety of citrate) measured in the presence of substrates that label acetyl-CoA in mitochondria only (ratio < 1.0) or in both mitochondria and peroxisomes (ratio > 1.0). The goals of the present study were to test, in rat livers perfused with [1-13 C]octanoate or [3-13 C]octanoate, (i) whether peroxisomal β-oxidation contributes acetyl groups for malonylCoA synthesis, and (ii) the degree of labelling homogeneity of acetyl-CoA proxies (acetyl moiety of citrate, acetate, β-hydroxybutyrate, malonyl-CoA and acetylcarnitine). Our data show that (i) octanoate undergoes two cycles of peroxisomal β-oxidation in liver, (ii) acetyl groups formed in peroxisomes contribute to malonyl-CoA synthesis, (iii) the labelling of acetyl-CoA proxies is markedly heterogeneous, and (iv) the labelling of C1 + 2 of β-hydroxybutyrate does not reflect the labelling of acetyl-CoA used in the citric acid cycle.

The fourth member of the beta(2)-integrin family of adhesion molecules, CD11d (alpha(D)beta(2)), is expressed on a wide variety of immune cells, however its function in autoimmune diseases, including EAE remains unknown. We induced EAE in wild-type and CD11d(-/-) C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide. The clinical course and histopathology of EAE were identical in both groups of mice throughout the disease course. There were no significant differences in the infiltration of leukocyte subsets into the central nervous system or in the production of cytokines from T cells isolated from the spleen or spinal cord from both groups of mice. Our data demonstrate that CD11d is not required for the development of EAE and, to date, is the only beta(2)-integrin molecule whose deletion does not result in attenuated disease.