Alteraciones en la homeostasis del colesterol hepático y sus implicaciones en la esteatohepatitis no alcohólica

Diversos estudios han demostrado que el colesterol libre (CL) hepático tiene una participación importante en la patogénesis de la esteatohepatitis no alcohólica (EHNA). Estos estudios han proporcionado evidencias de que la acumulación en el hígado de CL es tóxico a distintos niveles incluyendo: daño oxidativo a la mitocondria, estrés del retículo endoplasmático (RE) y activación de células de Kupffer (CKs) y células estelares hepáticas (CEH). En conjunto, estas evidencias sugieren que el contenido de CL hepático es importante en el inicio, mantenimiento y modulación de la respuesta inflamatoria asociada a la EHNA. En esta revisión, se discuten los distintos mecanismos participantes en la regulación de la homeostasis del colesterol y sus posibles implicaciones en el desarrollo y progresión del hígado graso no alcohólico (HGNA)

Relaxed targeting rules help PIWI proteins silence transposons

In eukaryotes, small RNA guides, such as small interfering RNAs and microRNAs, direct AGO-clade Argonaute proteins to regulate gene expression and defend the genome against external threats. Only animals make a second clade of Argonaute proteins: PIWI proteins. PIWI proteins use PIWI-interacting RNAs (piRNAs) to repress complementary transposon transcripts1,2. In theory, transposons could evade silencing through target site mutations that reduce piRNA complementarity. Here we report that, unlike AGO proteins, PIWI proteins efficiently cleave transcripts that are only partially paired to their piRNA guides. Examination of target binding and cleavage by mouse and sponge PIWI proteins revealed that PIWI slicing tolerates mismatches to any target nucleotide, including those flanking the scissile phosphate. Even canonical seed pairing is dispensable for PIWI binding or cleavage, unlike plant and animal AGOs, which require uninterrupted target pairing from the seed to the nucleotides past the scissile bond3,4. PIWI proteins are therefore better equipped than AGO proteins to target newly acquired or rapidly diverging endogenous transposons without recourse to new small RNA guides. Conversely, the minimum requirements for PIWI slicing are sufficient to avoid inadvertent silencing of host RNAs. Our results demonstrate the biological advantage of PIWI over AGO proteins in defending the genome against transposons and suggest an explanation for why the piRNA pathway was retained in animal evolution

Contribution of common genetic variants to obesity and obesity-related traits in mexican children and adults.

BACKGROUND: Several studies have identified multiple obesity-associated loci mainly in European populations. However, their contribution to obesity in other ethnicities such as Mexicans is largely unknown. The aim of this study was to examine 26 obesity-associated single-nucleotide polymorphisms (SNP) in a sample of Mexican mestizos. METHODS: 9 SNPs in biological candidate genes showing replications (PPARG, ADRB3, ADRB2, LEPR, GNB3, UCP3, ADIPOQ, UCP2, and NR3C1), and 17 SNPs in or near genes associated with obesity in first, second and third wave GWAS (INSIG2, FTO, MC4R, TMEM18, FAIM2/BCDIN3, BDNF, SH2B1, GNPDA2, NEGR1, KCTD15, SEC16B/RASAL2, NPC1, SFRF10/ETV5, MAF, PRL, MTCH2, and PTER) were genotyped in 1,156 unrelated Mexican-Mestizos including 683 cases (441 obese class I/II and 242 obese class III) and 473 normal-weight controls. In a second stage we selected 12 of the SNPs showing nominal associations with obesity, to seek associations with quantitative obesity-related traits in 3 cohorts including 1,218 Mexican Mestizo children, 945 Mexican Mestizo adults, and 543 Indigenous Mexican adults. RESULTS: After adjusting for age, sex and admixture, significant associations with obesity were found for 6 genes in the case-control study (ADIPOQ, FTO, TMEM18, INSIG2, FAIM2/BCDIN3 and BDNF). In addition, SH2B1 was associated only with class I/II obesity and MC4R only with class III obesity. SNPs located at or near FAIM2/BCDIN3, TMEM18, INSIG2, GNPDA2 and SEC16B/RASAL2 were significantly associated with BMI and/or WC in the combined analysis of Mexican-mestizo children and adults, and FTO locus was significantly associated with increased BMI in Indigenous Mexican populations. CONCLUSIONS: Our findings replicate the association of 8 obesity-related SNPs with obesity risk in Mexican adults, and confirm the role of some of these SNPs in BMI in Mexican adults and children

SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women

Background and aims. Secreted frizzled-related protein 5 (SFRP5) was recently described as a new adipokine protective for hepatic steatosis and other obesity-related complications in the mouse model. To date, SFRP5 expression in non-alcoholic fatty liver disease (NAFLD) has not been fully assessed in humans. We measured circulating SFRP5 levels and its expression in liver and adipose tissue, and evaluated its association with NAFLD in morbidly obese women.Material and methods. Fifty-four morbidly obese women undergoing bariatric surgery were included in the study. Liver biopsies were used for histology and hepatic triglyceride content quantification. Circulating SFRP5 levels were measured through enzyme-linked immunoabsorbent assay, and SFRP5 expression was performed in hepatic and adipose tissue (subcutaneous and visceral).Results. Although circulating SFRP5 levels showed a tendency to decrease with NAFLD progression, no significant differences were observed among non-alcoholic steatosis, steatohepatitis, and control subjects. Hepatic SFRP5 expression showed a negative correlation with hepatic triglyceride content (r = -0.349, P = 0.016 for mRNA and r = -0.291, P = 0.040 for SRFP5 protein) and ALT serum levels (r = -0.437, P = 0.001 for SRFP5 protein). In addition, hepatic SFRP5 protein levels were significantly lower in NASH than in control subjects (P = 0.006). Conclusion. This is the first study reporting an association of hepatic SFRP5 expression with NAFLD in humans

Associations of Candidate SNP loci with Obesity in the Mexican Population.

<p>Chr, chromosome; CI, confidence interval; OR, odds ratio; <i>P</i>-Het, <i>P</i>-heterogeneity. SNPs were ranked by <i>P</i>-values. Statistically significant associations are bold-faced. ^a<i>P</i>-values were adjusted for age and sex, and ^b<i>P</i>-values were further adjusted for admixture. All <i>P</i>-values were tested under an additive model (<i>P</i>_add), except those reported for <i>ADIPOQ</i>, <i>BCDIN3/FAIM2</i> and <i>BDNF</i> genes which were analyzed under a recessive model (<i>P</i>_rec).</p