A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.

It has been proposed that in autosomal recessive juvenile parkinsonism (AR-JP), a ubiquitin ligase (E3) Parkin, which is involved in endoplasmic reticulum-associated degradation (ERAD), lacks E3 activity. The resulting accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of Parkin, leads to endoplasmic reticulum stress, causing neuronal death. We previously reported that human E3 HRD1 in the endoplasmic reticulum protects against endoplasmic reticulum stress-induced apoptosis. This study shows that HRD1 was expressed in substantia nigra pars compacta (SNC) dopaminergic neurons and interacted with Pael-R through the HRD1 proline-rich region, promoting the ubiquitylation and degradation of Pael-R. Furthermore, the disruption of endogenous HRD1 by small interfering RNA (siRNA) induced Pael-R accumulation and caspase-3 activation. We also found that ATF6 overexpression, which induced HRD1, accelerated and caused Pael-R degradation; the suppression of HRD1 expression by siRNA partially prevents this degradation. These results suggest that in addition to Parkin, HRD1 is also involved in the degradation of Pael-R

Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure

Background: Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models. Methods and Findings: We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation. Conclusion: Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistanc

BABR increase energy expenditure.

<p>Hematoxylin and eosin (HE) stained epWAT (A) and BAT (B) sections of C57BL/6J animals treated with control or HF diet when indicated combined with colestimide or CA as specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1</a>. Scale bar, 50 µm. (C) BAT analysis by transmission electron microscopy. (D) Averaged O₂ consumption (VO₂) and CO₂ production (VCO₂) as measured by indirect calorimetry in mice on the different diets as indicated. Data are expressed as the mean +/− SEM (n = 5–6). * (<i>P</i><0.05) or ** (<i>P</i><0.01) versus F.</p

BA and BABR improve metabolic control in DIO C57BL/6J mice model.

<p>(A) Body weight, food intake and TG absorption (B) Liver, epididymal WAT (epWAT), and BAT weight change of C57BL/6J mice during 96 days on different diets. Ch stands for chow, F denotes HF diet, FCOL denotes HF diet+2.0% w/w colestimide and FB denotes HF diet+0.5% w/w CA. (C) Serum levels of TG, T-C, LDL-C, glucose and insulin in C57BL/6J mice on the indicated treatments. (D) Glucose levels during OGTT and IPITT in the different treatment groups (AUC is depicted in the inset). The OGTT were performed after an overnight fast after 9 weeks of administration. Glucose was administered by gavage at a dose of 2 g/kg. The IPITT were performed after 4 h fast after 10 weeks of administration. Insulin was injected at a dose of 0.75 U/kg. Data are expressed as the mean +/− SEM (n = 5–6). * (<i>P</i><0.05) or ** (<i>P</i><0.01) versus F.</p

Gene expression in liver, BAT, muscle and ileum.

<p>(A) mRNA expression levels of <i>Cyp7a1</i>, <i>Cyp8b1, Cyp27a1, Shp</i>, <i>Fxr</i>, <i>Pgc-1α</i>, <i>Pepck</i>, <i>G6Pase</i>, <i>Srebp-2</i>, HMG-CoA reductase, LDL-Receptor, <i>Pparα</i>, <i>Acc1</i> and <i>Scd1</i> were determined using quantitative RT-PCR in liver of C57BL/6J mice treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>. (B) mRNA expression levels of <i>D2</i>, <i>Pgc-1α</i> and <i>Ucp-1</i> in BAT. (C) <i>Pgc-1α</i> and <i>mCpt-1</i> in muscle. (D) <i>Fgf15</i> in ileum. Treatments and abbreviations are identical to those specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>. Mice were fasted 4 hours before sacrifice and tissue collection. Data are expressed as the mean +/− SEM (n = 5–6). * (<i>P</i><0.05) or ** (<i>P</i><0.01) versus F.</p

Bile acid composition in the enterohepatic organs and serum.

<p>Bile acid composition in the enterohepatic organs and serum of C57BL/6J fed with high fat diet (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>) after treatment with colestimide or CA. Undefined abbreviations are: G, glycol; T, tauro; CD, chenodeoxy; D, deoxy; H, hyo; HD, hyodeoxy; UD, ursodeoxy; L, litho; M, muri.</p

BA pool size and serum BA concentration in C57BL/6J mice.

<p>Ch denotes chow, F denotes HF diet, FCOL denotes HF diet+2% w/w colestimide and FB denotes HF diet+0.5% w/w CA as specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>.</p><p>Data are expressed as mean +/− SEM (n = 5–6).</p>A<p><i>P</i><0.05 versus F.</p>B<p><i>P</i><0.01 versus F.</p