Resmetirom for treatment of MASH.

Resmetirom is an oral selective THR-ß agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.

Cross talk between the liver microbiome and epigenome in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease), including its severe clinical forms, involves complex processes at all levels of biological organization. This study examined the potential link between the liver microbiome profile and epigenetic factors. METHODS: Liver microbial DNA composition was analysed using high throughput 16S rRNA gene sequencing in 116 individuals, with 55% being female, across the spectrum of liver disease severity. Total activity of histone deacetylases (HDACs) and acetyltransferases (HATs) was assayed in nuclear extracts from fresh liver samples. In addition, we measured the global 5-hydroxymethylcytosine (5-hmC) levels of liver DNA. FINDINGS: Patients with MASLD showed a 2.07-fold increase (p = 0.013) in liver total HAT activity. Moreover, a correlation was observed between liver total HAT activity and the score for histological steatosis (Spearman's R = 0.60, p = 1.0E-3) and disease severity (R = 0.40, p = 2.0E-2). Liver HAT and HDAC activities also showed associations with the abundance of several liver bacterial DNAs. Additionally, liver global levels of 5-hmC showed negative correlation with the read number of Bacteroidetes (R = -0.62, p = 9.3E-4) and Gammaproteobacteria (R = -0.43, p = 3.2E-2), while it was positively correlated with the abundance of Acidobacteria (R = 0.42, p = 4.1E-2) and Actinobacteria (R = 0.47, p = 1.8E-2). INTERPRETATION: The host liver epigenome, including the activity of enzymes involved in maintaining the balance between protein acetylation and deacetylation and the global DNA hydroxy-methylation status, may be the target of microbial signals. FUNDING: Agencia Nacional de Promoción Científica y Tecnológica, FonCyT.

The influence of host genetics on liver microbiome composition in patients with NAFLD.

BACKGROUND: Human body microbiotas are influenced by several factors, including the interaction of the host with the environment and dietary preferences. The role of host genetics in modulating the liver microbiota in the context of NAFLD remains unknown. To address this gap, we examined the interplay between the liver metataxonomic profile and host genetics. METHODS: We obtained 16S rRNA gene sequences from liver biopsies and genotypes by Taqman-assays in 116 individuals. We compared taxon abundance at the genus level across host genotypes using dominant models of inheritance. We focused the analysis on variants influencing the risk/ protection against NAFLD-histological severity (PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and HSD17B13-rs72613567) and a variant influencing macronutrient intake (FGF21-rs838133). We also explored the variants' combined effect via a polygenic risk score (PRS). FINDINGS: We identified at least 18 bacterial taxa associated with variants in the selected loci. Members of the Gammaproteobacteria class were significantly enriched in carriers of the rs738409 and rs58542926 risk-alleles, including Enterobacter (fold change [FC]=6.2) and Pseudoalteromonas (FC=2) genera, respectively. Lawsonella (1.6-FC), Prevotella_9 (FC=1.5), and Staphylococcus (FC=1.3) genera were enriched in rs838133-minor allele carriers, which is linked to sugar consumption and carbohydrate intake. Tyzzerella abundance (FC=2.64) exhibited the strongest association (p = 0.0019) with high PRS values (>4 risk alleles). The percentage of genus-level taxa variation explained by the PRS was ∼7.4%, independently of liver steatosis score and obesity. INTERPRETATION: We provided evidence that genetic variation may influence the liver microbial DNA composition. These observations may represent potentially actionable mechanisms of disease. FUNDING: This study was partially supported by grants PICT 2018-889, PICT 2019-0528, PICT2016-0135 and PICT 2018-0620 (Agencia Nacional de Promoción Científica y Tecnológica, FONCyT), CONICET Proyectos Unidades Ejecutoras 2017, PUE 0055.

Epigenetics factors in nonalcoholic fatty liver disease.

Introduction: Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors - defined as stable and heritable changes in gene expression without changes in the DNA sequence - may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage.Areas covered: By using systems biology approaches, we review the main epigenetic modifications and highlight their likely roles in the pathogenesis of nonalcoholic fatty liver disease.Expert opinion: Knowledge of the mechanisms by which epigenetic modifications participate in complex disorders would not only help scientists find novel therapeutic strategies but could also aid in implementing preventive care measures at gestation.

Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system.

Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits - a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits-specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.

Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.

INTRODUCTION: This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest. RESULTS: The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers. DISCUSSION: This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.

Cardiovascular and body weight regulation changes in transgenic mice overexpressing thyrotropin-releasing hormone (TRH).

Thyrotropin-releasing hormone (TRH) plays several roles as a hormone/neuropeptide. Diencephalic TRH (dTRH) participates in the regulation of blood pressure in diverse animal models, independently of the thyroid status. The present study aimed to evaluate whether chronic overexpression of TRH in mice affects cardiovascular and metabolic variables. We developed a transgenic (TG) mouse model that overexpresses dTrh. Despite having higher food consumption and water intake, TG mice showed significantly lower body weight respect to controls. Also, TG mice presented higher blood pressure, heart rate, and locomotor activity independently of thyroid hormone levels. These results and the higher urine noradrenaline excretion observed in TG mice suggest a higher metabolic rate mediated by sympathetic overflow. Cardiovascular changes were impeded by siRNA inhibition of the diencephalic Trh overexpression. Also, the silencing of dTRH in the TG mice normalized urine noradrenaline excretion, supporting the view that the cardiovascular effects of TRH involve the sympathetic system. Overall, we show that congenital dTrh overexpression leads to an increase in blood pressure accompanied by changes in body weight and food consumption mediated by a higher sympathetic overflow. These results provide new evidence confirming the participation of TRH in cardiovascular and body weight regulation.

Short-term doxorubicin cardiotoxic effects: involvement of cardiac Thyrotropin Releasing Hormone system.

Doxorubicin is an antineoplastic in the anthracycline class widely used for the treatment of several solid tumors and blood cancers. Cardiotoxicity is the major dose-limiting adverse effect of the drug. Chronic and accumulated doxorubicin administration cause myocyte damage and myocardial fibrosis. Doxorubicin-associated cardiotoxicity can be also observed after a short-course drug treatment even without clinical evidence of cardiac disease. Nevertheless, acute underlying mechanisms involved in the initiation of drug-induced cardiotoxicity remain poorly explored despite their similarities with pathophysiological conditions where cardiac TRH (cTRH) plays a central role. We showed that cTRH mediates myocardial injury induced by hypertension, and angiotensin II. Further, cTRH overexpression induces cardiac apoptosis, hypertrophy and fibrosis. AIM: To demonstrate that cTRH could mediate acute doxorubicin cardiotoxicity. MAIN METHOD: A single injection of doxorubicin (10 mg kg/day i.p.) was used to evaluate acute cardiac damage in a short-term experimental model of doxorubicin-induced cardiotoxicity. While inhibiting cTRH by small interfering RNA (siRNA), we evaluated the progression of cardiotoxicity. KEY FINDINGS: We found a doxorubicin-induced TRH overexpression in the LV, which was associated with apoptosis, hypertrophy and fibrosis. siRNA-mediated cTRH suppression prevented the doxorubicin-associated cardiac histological lesions. SIGNIFICANCES: doxorubicin requires an active cardiac TRH system to promote heart injury.

ADH1B∗2 Is Associated With Reduced Severity of Nonalcoholic Fatty Liver Disease in Adults, Independent of Alcohol Consumption.

BACKGROUND & AIMS: Alcohol dehydrogenase 1B (ADH1B) is involved in alcohol metabolism. The allele A (ADH1B∗2) of the rs1229984: A>G variant in ADH1B is associated with a higher alcohol metabolizing activity compared to the ancestral allele G (ADH1B∗1). Moderate alcohol consumption is associated with reduced severity of nonalcoholic fatty liver disease (NAFLD), based on histologic analysis, compared with no alcohol consumption. However, it is unclear whether ADH1B∗2 modifies the relationship between moderate alcohol consumption and severity of NAFLD. We examined the association between ADH1B∗2 and moderate alcohol consumption and histologic severity of NAFLD. METHODS: We collected data from 1557 multiethnic adult patients with biopsy-proven NAFLD enrolled into 4 different studies conducted by the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network. Histories of alcohol consumption were obtained from answers to standardized questionnaires. Liver biopsy samples were analyzed by histology and scored centrally according to the NASH Clinical Research Network criteria. We performed covariate adjusted logistic regressions to identify associations between histologic features of NAFLD severity and moderate alcohol consumption and/or ADH1B∗2. RESULTS: A higher proportion of Asians/Pacific Islanders/Hawaiians carried the ADH1B∗2 allele (86%) than other racial groups (4%-13%). However, the study population comprised mostly non-Hispanic whites (1153 patients, 74%), so the primary analysis focused on this group. Among them, 433 were moderate drinkers and 90 were ADH1B∗2 carriers. After we adjusted for confounders, including alcohol consumption status, ADH1B∗2 was associated with lower frequency of steatohepatitis (odds ratio [OR], 0.52; P < .01) or fibrosis (odds ratio, 0.69; P = .050) compared with ADH1B∗1. Moderate alcohol consumption (g/d) reduced the severity of NAFLD in patients with ADH1B∗1 or ADH1B∗2. However, ADH1B∗2, compared to ADH1B∗1, was associated with a reduced risk of definite NASH (ADH1B∗2: OR, 0.80; P < .01 vs ADH1B∗1: OR, 0.96; P = .036) and a reduced risk of an NAFLD activity score of 4 or higher (ADH1B∗2: OR, 0.83; P = .012 vs ADH1B∗1: OR, 0.96; P = .048) (P < .01 for the difference in the effect of moderate alcohol consumption between alleles). The relationship between body mass index and NAFLD severity was significantly modified by ADH1B∗2, even after we controlled for alcohol consumption. CONCLUSIONS: ADH1B∗2 reduces the risk of NASH and fibrosis in adults with NAFLD regardless of alcohol consumption status. ADH1B∗2 might modify the association between high body mass index and NAFLD severity.

Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease.

OBJECTIVE: We aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosis, as differences in the host phenotypic features-from moderate to severe obesity-may be associated with significant changes in the microbial DNA profile. DESIGN AND METHODS: Liver tissue samples from 116 individuals, comprising of 47 NAFLD overweight or moderately obese patients, 50 NAFLD morbidly obese patients elected for bariatric surgery and 19 controls, were analysed using high-throughput 16S rRNA gene sequencing. RESULTS: Liver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Bacteroidetes (p=1.8e-18) and Firmicutes (p=0.0044) were over-represented in morbidly obese patients and Proteobacteria (p=5.2e-10)-specifically Gammaproteobacteria and Alphaproteobacteria, and Deinococcus-Thermus (p=0.00012)-were over-represented in the non-morbidly obese cohort. Cohort-specific analysis of liver microbial DNA signatures shows patterns linked to obesity. The imbalance in Proteobacteria (Alpha or Gamma) among non-morbidly obese patients, and Peptostreptococcaceae, Verrucomicrobia, Actinobacteria and Gamma Proteobacteria DNA among morbidly obese patients was associated with histological severity. Decreased amounts of bacterial DNA from the Lachnospiraceae family were associated with more severe histological features. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences. CONCLUSION: This is the first comprehensive study showing that the liver tissue of NAFLD patients contains a diverse repertoire of bacterial DNA (up to 2.5×104 read counts). The liver metataxonomic signature may explain differences in the NAFLD pathogenic mechanisms as well as physiological functions of the host.

Angiotensin II requires an intact cardiac thyrotropin-releasing hormone (TRH) system to induce cardiac hypertrophy in mouse.

Cardiac tyhrotropin-releasing hormone (TRH) is overexpressed in the hypertrophied left ventricle (LV) of spontaneously hypertensive rats (SHR) and its inhibition prevents both hypertrophy and fibrosis. In a normal heart, the TRH increase induces fibrosis and hypertrophy opening the question of whether TRH could be a common mediator of left ventricular hypertrophy (LVH). We used angiotensin II (AngII) as an inductor of LVH to evaluate if the blockade of LV-TRH prevents hypertrophy and fibrosis in mice. We challenged C57BL/6 adult male mice with an infusion of AngII (osmotic pumps; 2 mg/kg.day) to induce LVH. Groups of mice were injected with an intracardiac siRNA-TRH or scrambled siRNA (siRNA-Con). Body weight, water intake and systolic arterial blood pressure (SABP) were measured daily. AngII significantly increased water intake and SABP (p < .05). Cardiac hypertrophy (heart weight/body weight) was evident in the group with the normal cardiac TRH system. In fact, it was found an AngII-induced increase of TRH precursor mRNA (p < .05) in conjunction with elevated TRH levels measured by immunohistochemistry and western blot. These changes were not observed in the AngII + siRNA-TRH group. Furthermore, AngII increased significantly (p < .05) BNP (hypertrophic marker), collagens I and III and TGF-ß (fibrosis markers) expression in the group with the native cardiac TRH system. These increases were attenuated in the groups with the TRH system blocked despite the high blood pressure. Similar and stronger results were observed "in vitro" with NIH3T3 and H9C2 cell culture models, where, when the TRH system is blocked, AngII stimulus was not able to induce the markers of its fibrotic and hypertrophic effects, so we believe that these effects are independent of any other physiological modifications. Our results point out that cardiac TRH is required for AngII-induced hypertrophic and fibrotic effects.

Serotonin-transporter promoter polymorphism modulates the ability to control food intake: Effect on total weight loss.

SCOPE: The biggest challenge for losing weight is the ability to control the amount of food eaten; the tendency to overeat is called disinhibition. Our aims were to determine whether (a) the SLC6A4-promoter variant (5-HTTLPR) relates to disinhibition; (b) this association could affect total weight-loss during a behavioral/dietary treatment for obesity. METHODS AND RESULTS: A total of 2961 subjects attended voluntarily five weight-loss clinics; a subsample (n = 624) was recruited for SLC6A4 genotyping. Total weight-loss, emotional-eating-score and disinhibition-score were examined. We observed that: (a) the reduced ability to control food intake (disinhibition) is implicated in the impairment to lose weight; (b) SLC6A4-promoter variant is implicated in disinhibition. S carriers (low-expressing) of the SLC6A4-promoter variant had a lower inhibition capacity and showed more failure (1.6 times) to control the amount of food eaten than LL (p < 0.05); other factors such as eating while bored, overeating after work at night, or craving for specific foods were associated to the SLC6A4 genotype (p < 0.05); (c) The combination of disinhibition (high disinhibition) and genetics (S carrier) had a higher impact on total weight loss than each factor separately. CONCLUSIONS: SLC6A4-promoter variant is associated with the ability to control food intake and interacts with emotional eating to modulate total weight loss.

Epigenética y síndrome metabólico / Epigenetics and Metabolic Syndrome

La epigenética puede definirse como los cambios estables y heredables en la expresión génica, que no son producidos por cambios en la secuencia del ADN. Las modificaciones epigenéticas más estudiadas son la metilación del ADN y las modificaciones postraduccionales de histonas. Estas podrían explicar cómo factores ambientales, nutricionales y otros, contribuyen a la modulación de la expresión de genes y al desarrollo de distintas enfermedades. El síndrome metabólico está definido por la presencia de obesidad, fundamentalmente central, hipertensión, diabetes, dislipemia, y un estado protrombótico y proinflamatorio, que son factores de riesgo de enfermedad cardiovascular. La genética de estas enfermedades es compleja, y es sabido que tanto factores genéticos de susceptibilidad o resistencia, como factores ambientales contribuyen al desarrollo de este síndrome. Nuestro grupo ha estudiado la participación de las modificaciones epigenéticas en la fisio­patología del síndrome metabólico. Ellas podrían tener un rol importante no solo en el desarrollo de estas enfermedades en la vida adulta, sino predisponer al individuo desde desarrollo prenatal. En esta revisión describimos las principales modificaciones epigenéticas, y a través de nuestros hallazgos cómo sería su papel en el desarrollo del síndrome metabólico. Conocer cómo participarían las modificaciones epigenéticas en estas enfermedades, no solo permitirá mejorar el tratamiento de las mismas, sino establecer medidas preventivas desde la gestación. Rev Argent Endocrinol Metab 52:35-44, 2015 Los autores declaran no poseer conflictos de interés.

Epigenetics can be defined as stable and heritable changes in gene expression that are not produced by changes in DNA sequence. The most studied epigenetic modifications are DNA methylation and histone post-translational modifications. Epigenetic modifications might explain how environmental, nutritional and others factors contribute to the modulation of gene expression and the development of different diseases. Metabolic syndrome is defined by the presence of mainly central obesity, hypertension, diabetes, dyslipidemia, and a prothrombotic and proinflammatory state, which are risk factors for cardiovascular disease. The genetic factors of these diseases are complex, and it is known that genetic susceptibility or resistance backgrounds as well as environmental factors contribute to the development of this syndrome. We have studied the in­volvement of epigenetic modifications in the pathophysiology of metabolic syndrome. These modifications might play an important role in the development of these diseases in adulthood, and according to our results, they might also predispose an individual from prenatal life. In this review, we describe the main epigenetic modifications, and which could be their role in the development of metabolic syndrome. Understanding how epigenetic modifications act in these diseases could not only help to identify new avenues of treatment but also to establish preventive measures from gestation. Rev Argent Endocrinol Metab 52:35-44, 2015 No financial conflicts of interest exist.

Fatty liver is associated with transcriptional downregulation of stearoyl-CoA desaturase and impaired protein dimerization.

AIMS AND METHODS: We evaluated the modulation of liver stearoyl-CoA desaturase-1 (Scd1) by dietary factors and insulin resistance (IR) in two experimental models of high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). The first model included Sprague Dawley (SD) rats that developed NAFLD without IR, and the second one included a rat model of genetic IR and cardiovascular disease, the spontaneously hypertensive rats (SHR) and its normotensive, insulin-sensitive control Wistar-Kyoto (WKY). The adult rats were given standard chow diet (CD) or HFD for 10 weeks. In all the animals, we explored the hepatic Scd1 transcriptional activity and protein levels. RESULTS: HFD-fed rats of both strains developed severe NAFLD. Liver abundance of Scd1 mRNA was significantly decreased in HFD-fed rats regardless of the strain; SD-CD: 235±195 vs. SD-HFD 4.5±2.9, p<0.0004, and SHR-CD: 75.6±10.8 vs. SHR-HFD: 4.48±17.4, and WKY-CD: 168.7±17.4 vs. WKY-HFD: 12.9±17.4, p<0.000001 (mean±SE, ANCOVA adjusted by HOMA). Analysis of liver Scd1 protein expression showed a particular pattern in the HFD groups, characterized by the presence of high levels of a monomeric protein band (32.2-36.6 Kda, p<0.003) and decreased levels of a dimeric protein band (61.9-66.1 Kda, p<0.02) regardless of the rat strain. Pharmacologic intervention with the peroxisome proliferator-activated receptor α agonist clofibrate reverted the liver phenotype and significantly modified the hepatic Scd1 transcriptional activity and protein expression. CONCLUSION: Diet-induced fatty liver is associated with the downregulation of hepatic Scd1 transcript and de-dimerization of the protein, and these changes were not much affected by the status of peripheral IR.

Maternal high-fat intake during pregnancy programs metabolic-syndrome-related phenotypes through liver mitochondrial DNA copy number and transcriptional activity of liver PPARGC1A.

UNLABELLED: In this study, we contrasted the hypothesis that maternal diet during pregnancy has an impact on fetal metabolic programming through changes in liver mitochondrial DNA (mtDNA) content and transcriptional activity of Ppargc1a and that these effects are sex specific. METHODS: Rats were fed either high-fat (HFD) or standard chow diet (SCD) during gestation and lactation. The resulting adult male and female offspring were fed either HFD or SCD for an 18-week period, generating eight experimental groups. RESULTS: Maternal HFD feeding during pregnancy is associated with a decreased liver mtDNA copy number (P<.008). This effect was independent of the offspring sex or diet, and was significantly associated with fatty liver when dams were fed HFD (P<.05, adjusted by homeostasis model assessment of insulin resistance, HOMA-IR). We also found that maternal HFD feeding results in a male-specific significant reduction of the liver abundance of Ppargc1a mRNA (P<.004), which significantly impacted peripheral insulin resistance. Liver expression of Ppargc1a was inversely correlated with HOMA-IR (R=-0.53, P<.0003). Only male offspring exposed to a chronic metabolic insult in adult life were insulin resistant and hyperleptinemic, and showed abnormal liver and abdominal fat accumulation. Liver abundance of Tfam, Nrf1, Hnf4a, Pepck and Ppparg mRNA was not associated with maternal programming. In conclusion, maternal high-fat diet feeding during pregnancy programs liver mtDNA content and the transcriptional activity of Ppargc1a, which strongly modulates, in a sex-specific manner, glucose homeostasis and organ fat accumulation in adult life after exposure to a nutritional insult.

Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease.

OBJECTIVE & DESIGN: Nonalcoholic fatty liver disease (NAFLD) is a clinical condition that refers to progressive histological changes ranging from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). We evaluated the status of cytosine methylation (5mC) of liver mitochondrial DNA (mtDNA) in selected regions of the mtDNA genome, such as D-loop control region, and mitochondrially encoded NADH dehydrogenase 6 (MT-ND6) and cytochrome C oxidase I (MT-CO1), to contrast the hypothesis that epigenetic modifications play a role in the phenotypic switching from SS to NASH. METHODS: We studied liver biopsies obtained from patients with NAFLD in a case-control design; 45 patients and 18 near-normal liver-histology subjects. RESULTS: MT-ND6 methylation was higher in the liver of NASH than SS patients (p < 0.04) and MT-ND6 methylated DNA/unmethylated DNA ratio was significantly associated with NAFLD activity score (p < 0.02). Liver MT-ND6 mRNA expression was significantly decreased in NASH patients (0.26 ± 0.30) versus SS (0.74 ± 0.48), p < 0.003, and the protein level was also diminished. The status of liver MT-ND6 methylation in NASH group was inversely correlated with the level of regular physical activity (R = -0.54, p < 0.02). Hepatic methylation levels of D-Loop and MT-CO1 were not associated with the disease severity. DNA (cytosine-5) methyltransferase 1 was significantly upregulated in NASH patients (p < 0.002). Ultrastructural evaluation showed that NASH is associated with mitochondrial defects and peroxisome proliferation. CONCLUSION: Hepatic methylation and transcriptional activity of the MT-ND6 are associated with the histological severity of NAFLD. Epigenetic changes of mtDNA are potentially reversible by interventional programs, as physical activity could modulate the methylation status of MT-ND6.

Genetic determinants of acquired cholestasis: a systems biology approach.

Cholestatic liver diseases encompass a complex spectrum of intrahepatic and cholangiocellular cholestasis, whose etiologies include genetic and environmental components. This review focuses on the role of the genetic component of three adult cholestatic diseases, namely, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and intrahepatic cholestasis of pregnancy (ICP). In particular, we integrate genomic, molecular, and physiological data to understand the putative interplay between the underlying genetic mechanisms involved in the susceptibility of these diseases. This approach is based on the hypothesis that a more integrative knowledge of the genetic determinants of cholestatic diseases may have a strong impact on the development of improved therapies. We also propose the strategy of gene prioritization to identity potential candidate genes for disease susceptibility, and show some examples of "leading genes of human cholestatic pathways". Finally, based on the hypothesis that common physiologic processes and molecular networks may influence the risk of adult cholestatic diseases, we used a candidate gene prioritization application based on the use of a protein-protein interaction network as part of the 'interactome'.

Odor perception between heterosexual partners: its association with depression, anxiety, and genetic variation in odorant receptor OR7D4.

We performed a study on a sample of 856 individuals to answer whether the pleasantness/unpleasantness of the odor perception of their partners (rating of partner odor) is associated with depression and anxiety. To evaluate the influence of common genetic variation of the odorant receptor OR7D4 on the rating of partner odor, the variant rs8109935 was genotyped in the whole sample. The rating of partner odor was significantly associated with scores of anxiety and depression. Depression (OR: 0.75, 95% CI: 0.56-0.98, p = 0.039) and anxiety (Robust Coef ± SE: -13 ± 0.6, p = 0.044) were inversely associated with pleasantness rating of partner odor. Ordered probit regression analysis shows that the rating of partner odor was significantly associated with the rs8109935 genotypes (Coef ± robust SE: 0.19 ± 0.09, p = 0.028). These findings suggest that odor perception between heterosexual partners may have an impact on the development of depression and anxiety, and that it might be influenced by genetic variation in OR7D4.

Gene-gene interaction between serotonin transporter (SLC6A4) and CLOCK modulates the risk of metabolic syndrome in rotating shiftworkers.

Serotonergic neurotransmission and the master circadian CLOCK gene are physiological modulators of the circadian system. In addition, both are involved in the physiopathology of metabolic syndrome (MS). The authors sought to examine the potential effect of the gene-gene interaction between the functional 44-bp insertion/deletion polymorphism in the promoter region (serotonin-transporter-linked promoter region polymorphism or 5-HTTLPR) of the serotonin transporter gene (SLC6A4) and common variants of the gene CLOCK on the genetic risk underlying MS of shift-workers. To test this hypothesis, 856 men were studied; 518 dayworkers were compared with 338 rotating shiftworkers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health-related behaviors, and biochemical determinations were obtained from every participant. 5-HTTLPR genotypes were determined using polymerase chain reaction followed by gel electrophoresis. Six tag single-nucleotide polymorphisms (SNPs) in the CLOCK gene with a minor allele frequency >10 % (rs1554483 C/G, rs11932595 A/G, rs4580704 C/G, rs6843722 A/C, rs6850524 C/G, and rs4864548 A/G), encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r(2) > .8), were genotyped. A significant interaction between the 5-HTTLPR variant and the haplotype rs1554483-rs4864548 of the CLOCK gene was detected for diastolic (p = .0058) and systolic blood pressure (p = .0014), arterial hypertension (p = .033), plasma triglycerides levels (p = .033), and number of MS components (p = .01). In all these cases, the higher values were observed in rotating shiftworkers homozygous for the SLC6A4 S allele and carrying the haplotype composed by the CLOCK rs1554483 G and rs4864548 A variants. In conclusion, these data suggest a potential interaction (epistatic effect) of serotonin transporter and CLOCK gene variation on the genetic susceptibility to develop MS by rotating shiftworkers.