Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach

Elevated serum uric acid (SUA)—hyperuricemia—is caused by overproduction of urate or by its decreased renal and/or intestinal excretion. This disease, which is increasing in prevalence worldwide, is associated with both gout and metabolic diseases. Several studies have reported relationships between apolipoprotein E (APOE) haplotypes and SUA levels in humans; however, their results remain inconsistent. This prompted us to investigate the relationship between APOE polymorphisms and SUA levels. Our subjects were 5,272 Japanese men, premenopausal women, and postmenopausal women. Multiple linear regression analyses revealed the ε2 haplotype of APOE to be independently associated with higher SUA in men (N = 1,726) and postmenopausal women (N = 1,753), but not in premenopausal women (N = 1,793). In contrast, the ε4 haplotype was little related to SUA levels in each group. Moreover, to examine the effect of Apoe deficiency on SUA levels, we conducted animal experiments using Apoe knockout mice, which mimics ε2/ε2 carriers. We found that SUA levels in Apoe knockout mice were significantly higher than those in wild-type mice, which is consistent with the SUA-raising effect of the ε2 haplotype observed in our clinico-genetic analyses. Further analyses suggested that renal rather than intestinal underexcretion of urate could be involved in Apoe deficiency-related SUA increase. In conclusion, we successfully demonstrated that the ε2 haplotype, but not the ε4 haplotype, increases SUA levels. These findings will improve our understanding of genetic factors affecting SUA levels.

Mechanism of bilirubin elimination in urine: insights and prospects for neonatal jaundice

Despite a century of research, bilirubin metabolism and the transport mechanisms responsible for homeostasis of bilirubin in serum remain controversial. Emerging evidence on the hepatic membrane transporters and inherited disorders of bilirubin metabolism have contributed to a greater understanding of the various steps involved in bilirubin homeostasis and its associated excretory pathways. We discuss these recent research findings on hepatic membrane transporters and evaluate their significance on the newborn bilirubin metabolism and excretion. New insights gained speculate that a proportion of conjugated bilirubin is excreted via the renal system, as an alternative to the intestinal excretion, even in normal physiological jaundice with no associated pathological concerns. Finally, this paper discusses the clinical relevance of targeting the altered renal excretory pathway, as bilirubin in urine may hold diagnostic importance in screening for neonatal jaundice.

Hypolipidemic Roles of Casein-Derived Peptides by Regulation of Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis

Hyperlipidemia, a syndrome characterized by an abnormal elevation of blood lipids, causes chronic lethal metabolic disorders. Although statins are regularly prescribed to patients, an alternative to treat the burden of excessive lipids is required for cholesterol control. In this study, it was found that the treatment of casein hydrolyzed by pepsin and trypsin induced trans-intestinal cholesterol excretion (TICE) through ATP-binding cassette subfamily G members 5 (ABCG5) expression. Next, we analyzed sequences of the peptides responsible for TICE induction, synthesized artificial peptides based on the sequences, and the hypolipidemic effects of the peptide treatments were assessed in both in vitro and in vivo models. We determined that two bioactive peptides contained in casein hydrolysates (SQSKVLPVPQK and HPHPHLSF) induced TICE through the expression of ABCG5 in enterocytes and suppressed hepatic mRNA expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1by ileal FGF19 expression both in an liver X receptor α (LXRα)-mediated manner. In the hyperlipidemic mouse models, the oral administration of peptides reduced serum cholesterol levels through elevation of the ABCG5 expression in proximal intestine and fecal cholesterol secretion. Besides this, peptides induced ileal expression of fibroblast growth factor 15/19 (FGF15/19) and inhibited hepatic bile acid synthesis. We found that the oral treatment of casein-derived bioactive peptides could improve hyperlipidemia by regulating intestinal excretion and hepatic synthesis of cholesterols.

Dendrobium officinale Six nostrum promotes excretion of intestinal uric acid in hyperuricemia rat through inhibiting LPS/TLR4/NF-κB signaling pathway

Background : To evaluate the effect of Dendrobium officinale Six nostrum (DOS) on promoting the intestinal excretion of uric acid (UA) in the rat model of hyperuricemia (HUA), and explored its possible mechanisms of action. Methods: In this study, HUA was induced in rat by administration of lipid emulsion (LE) for 6 weeks, meanwhile, the rat was orally administered with DOS for 6 weeks. Then the level of serum uric acid (SUA) and fecal uric acid (FUA) were measured by automatic biochemical analyzer. Lipopolysaccharide (LPS) in hepatic portal vein blood was detected by ELISA kit. The intestinal protein levels of ATP-binding cassette superfamily G member 2 (ABCG2) and glucose transporter 9 (GLUT9) were measured by Western blot assay. Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-κB) were determined by immunohistochemistry (IHC). Hematoxylin and eosin (H&E) staining was used to assess intestinal histological changes. Meanwhile, the main compositions of DOS were identified and determined by the High Performance Liquid Chromatography (HPLC). Results: According to HPLC analysis, acteoside and astilbin were identified as the main chemical components of DOS. Our results indicated that DOS significantly reduced SUA level and increased FUA level in the HUA rat induced by oral administration of LE for 6 weeks. IHC and Western blot showed that DOS could significantly increase protein level of ABCG2 and reduce protein level of GLUT9 in the intestine. It remarkably reduced the content of LPS in hepatic portal vein blood and decrease protein levels of TLR4 and NF-κB in the intestine. In addition, DOS could improve the histopathological changes of intestine through increasing the number of intestinal gland goblet cells, and recovering the complete and neatly-arranged structure of small intestinal epithelial cells. Conclusions: DOS has the effect of treating hyperuricemia, the molecular mechanism may be associated with up-regulating ABCG2 protein level, and down-regulating protein level of GLUT9 in the intestine to promote the intestinal excretion of UA, and then decreasing the SUA level. In addition, DOS can reduce the damage of inflammatory response to the intestine, improve the histopathological changes of intestine in HUA rat through inhibiting LPS/TLR4/NF-κB inflammatory pathway.

Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2

Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe−/− mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe−/− mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe−/− mice, the enzymatic activity was higher in Hfe−/− mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe−/− mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe−/− mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.