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- Laplante, Mathieu, et al.
(author)
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Tissue-specific postprandial clearance is the major determinant of PPARgamma-induced triglyceride lowering in the rat
- 2009
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - Bethesda, Md. : American Physiological Society. - 0363-6119 .- 1522-1490. ; 296:1, s. R57-R66
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Journal article (peer-reviewed)abstract
- Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonism potently reduces circulating triglycerides (TG) in rodents and more modestly so in humans. This study aimed to quantify in vivo the relative contribution of hepatic VLDL-TG secretion and tissue-specific TG clearance to such action. Rats were fed an obesogenic diet, treated with the PPARgamma full agonist COOH (30 mg.kg(-1).day(-1)) for 3 wk, and studied in both the fasted and refed (fat-free) states. Hepatic VLDL-TG secretion rate was not affected by chronic COOH in the fasted state and was only modestly decreased (-30%) in refed rats. In contrast, postprandial VLDL-TG clearance was increased 2.6-fold by COOH, which concomitantly stimulated adipose tissue TG-derived lipid uptake and one of its major determinants, lipoprotein lipase (LPL) activity, in a highly depot-specific manner. TG-derived lipid uptake and LPL were indeed strongly increased in subcutaneous inguinal white adipose tissue and in brown adipose tissue, independently of the nutritional state, whereas of the three visceral fat depots examined (epididymal, retroperitoneal, mesenteric) only the latter responded consistently to COOH. Robust correlations (0.5 < r < 0.9) were observed between TG-derived lipid uptake and LPL in adipose tissues. The agonist did not increase LPL in muscle, and its enhancing action on postprandial muscle lipid uptake appeared to be mediated by post-LPL processes involving increased expression of fatty acid binding/transport proteins (aP2, likely in infiltrated adipocytes, FAT/CD36, and FATP-1). The study establishes in a diet-induced obesity model the major contribution of lipid uptake by specific, metabolically safe adipose depots to the postprandial hypotriglyceridemic action of PPARgamma agonism, and suggests a key role for LPL therein.
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| 2. |
- Ohta, Yasuyuki, et al.
(author)
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Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis
- 2016
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In: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 25:21, s. 4771-4786
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Journal article (peer-reviewed)abstract
- Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.
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