Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans.

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Nitrooxidative Stress and Neuroinflammation Caused by Air Pollutants Are Associated with the Biological Markers of Neurodegenerative Diseases.

Millions of people around the world are exposed to air pollutants, such as particulate matter 2.5 (PM2.5) and ozone (O3). Such exposure usually does not exclude these two types of pollutants and their harmful effects could be additive or synergistic. O3 is a highly oxidizing gas that reacts with the cellular environment just as PM2.5, triggering nitrooxidative damage. Once nitrooxidative stress overcomes the endogenous antioxidant system, an acute neuroinflammatory process is generated, and once it becomes chronic, it favors the formation of neurodegenerative disease markers. The presence of these markers becomes potentially dangerous in people who have a genetic predisposition and are at a higher risk of developing neurodegenerative diseases such as Alzheimer's and Parkinson's. Our experimental approach for nitrooxidative damage and neuroinflammation caused by air pollutants has focused on the exposure of rats to O3 in an isolated chamber. The hippocampus is the most studied brain structure because of its neuronal connectivity network with the olfactory epithelium, its weak antioxidant defense, and its fundamental roll in cognitive processes. However, other brain structures may exhibit a different degree of damage upon exposure to O3 and PM2.5, making their involvement an important factor in developing other CNS diseases. The age spectrum for augmented sensibility to air pollutants seems to mostly affect the pre-postnatal (autism spectrum) period and the elderly (neurodegenerative). Thus, a new approach could be the estimation of the damage caused by PM2.5 and O3 through a controlled exposure paradigm to determine the extent of damage caused by both pollutants.

Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer.

Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the "cancer hallmarks" of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.

Association between the rs3812316 Single Nucleotide Variant of the MLXIPL Gene and Alpha-Linolenic Acid Intake with Triglycerides in Mexican Mestizo Women.

The carbohydrate response element binding protein (ChREBP) is a key transcription factor to understand the gene−diet−nutrient relationship that leads to metabolic diseases. We aimed to analyze the association between the rs17145750 and rs3812316 SNVs (single nucleotide variants) of the MLXIPL gene with dietary, anthropometric, and biochemical variables in Mexican Mestizo subjects. This is a cross-sectional study of 587 individuals. Genotyping was performed by allelic discrimination. In addition, liver and adipose tissue biopsies were obtained from a subgroup of 24 subjects to analyze the expression of the MLXIPL gene. An in silico test of the protein stability and allelic imbalance showed that rs17145750 and rs3812316 showed a high rate of joint heritability in a highly conserved area. The G allele of rs3812316 was associated with lower triglyceride levels (OR = −0.070 ± 0.027, p < 0.011, 95% CI = −0.124 to −0.016), the production of an unstable protein (ΔΔG −0.83 kcal/mol), and probably lower tissue mRNA levels. In addition, we found independent factors that also influence triglyceride levels, such as insulin resistance, HDL-c, and dietary protein intake in women. Our data showed that the association of rs3812316 on triglycerides was only observed in patients with an inadequate alpha-linolenic acid intake (1.97 ± 0.03 vs. 2.11 ± 0.01 log mg/dL, p < 0.001).

Effect of Lupinus rotundiflorus gamma conglutin treatment on JNK1 gene expression and protein activation in a rat model of type 2 diabetes.

CONTEXT: Gamma conglutin (Cγ) from lupine species represents a potential complementary treatment for type 2 diabetes mellitus (T2DM) because of its hypoglycaemic effect. However, its underlying mechanism of action is not fully known. OBJECTIVE: To evaluate whether Cγ from Lupinus rotundiflorus M. E. Jones (Fabaceae) modulates c-Jun N-terminal kinase 1 (JNK1) expression and activation in a T2DM rat model. MATERIALS AND METHODS: Gamma conglutin isolated from L. rotundiflorus seeds was characterized by SDS-PAGE. Fifteen Wistar rats with streptozotocin-induced T2DM (HG) were randomized into three groups (n = 5): vehicle administration (HG-Ctrl), oral treatment with Cγ (120 mg/kg/day) (HG-Lr) for one week, and treatment with metformin (300 mg/kg/day) (HG-Met); a healthy group (Ctrl, n = 5) was included as control. The levels of glucose and biomarkers of renal and hepatic function were measured pre- and post-treatment. Hepatic Jnk1 expression and phosphorylation of JNK1 were evaluated by qRT-PCR and western blot, respectively. RESULTS: Oral treatment with either Cγ or metformin reduced serum glucose level to 86.30 and 74.80 mg/dL, respectively (p ˂ 0.05), from the basal levels. Jnk1 expression was 0.65- and 0.54-fold lower (p ˂ 0.05) in the HG-Lr and HG-Met groups, respectively, than in HG-Ctrl. Treatment with Cγ decreased JNK1 phosphorylation. However, Cγ did not change the levels of kidney and liver biomarkers. DISCUSSION AND CONCLUSIONS: Treatment with Cγ from L. rotundiflorus inhibited Jnk1 expression, in vivo, suggesting JNK1 as a potential therapeutic target in diabetes and revealing one mechanism underlying the hypoglycaemic effect of lupine Cγ. Nevertheless, further studies are required.

Association of the PNPLA2, SCD1 and Leptin Expression with Fat Distribution in Liver and Adipose Tissue From Obese Subjects.

The expansion of adipose tissue is regulated by insulin and leptin through sterol regulatory element-binding protein-1c (SREBP-1c), up-regulating lipogenesis in tissues by Stearoylcoenzyme A desaturase 1 (SCD1) enzyme, while adipose triglyceride lipase (ATGL) enzyme is key in lipolysis. The research objective was to evaluate the expression of Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1), SCD1, Patatin Like Phospholipase Domain Containing 2 (PNPLA2), and leptin (LEP) genes in hepatic-adipose tissue, and related them with the increment and distribution of fat depots of individuals without insulin resistance. Thirty-eight subjects undergoing elective cholecystectomy with liver and adipose tissue biopsies (subcutaneous-omental) are included. Tissue gene expression was assessed by qPCR and biochemical parameters determined. Individuals are classified according to the body mass index, classified as lean (control group, n=12), overweight (n=11) and obesity (n=15). Abdominal adiposity was determined by anthropometric and histopathological study of the liver. Increased SCD1 expression in omental adipose tissue (p=0.005) and PNPLA2 in liver (p=0.01) were found in the obesity group. PNPLA2 decreased expression in subcutaneous adipose tissue was significant in individuals with abdominal adiposity (p=0.017). Anthropometric parameters positively correlated with liver PNPLA2 and the expression of liver PNPLA2 with serum leptin. SCD1 increased levels may represent lipid storage activity in omental adipose tissue. Liver PNPLA2 increased expression could function as a primary compensatory event of visceral fat deposits associated to the leptin hormone related to the increase of adipose tissue.

Expression of the receptor of advanced glycation end-products (RAGE) and membranal location in peripheral blood mononuclear cells (PBMC) in obesity and insulin resistance.

OBJECTIVES: The present study aimed to evaluate the receptor of advanced glycation end-products (RAGE), NF-kB, NRF2 gene expression, and RAGE cell distribution in peripheral blood mononuclear cells (PBMC) in subjects with obesity and IR compared with healthy subjects. MATERIALS AND METHODS: The mRNA expression levels of RAGE, NF-kB, NRF2, and GAPDH were determined in PBMC by qPCR in 20 obese (OB), 17 obese with insulin resistance (OB-IR), and 20 healthy subjects (HS), matched by age and sex. RAGE protein expression and its localization were determined by Western Blot and immunocytochemistry (ICC) analysis, total soluble RAGE (sRAGE) and MCP-1 plasma levels by ELISA. RESULTS: RAGE, NF-kB, and NRF2 genes mRNA expression in PBMCs did not show variation between groups. RAGE protein was lower in OB and OB-IR groups; RAGE was located predominantly on the cell-surface in the OB-IR group compared to the HS group (22% vs 9.5%, P<0.001). OB-IR group showed lower sRAGE plasma levels, and correlated negatively with HOMA-IR, ALT parameters (r= -0.374, r= -0.429, respectively), and positively with NFE2L2 mRNA (r= 0.540) P<0.05. CONCLUSION: In this study, OB-IR subjects did not reflect significant differences in gene expression; however, correlations detected between sRAGE, biochemical parameters, and NRF2, besides the predominant RAGE distribution on the cell membrane in PBMC could be evidence of the early phase of the inflammatory cascade and the subsequent damage in specific tissues in subjects with OB-IR.

Development of an effective and rapid qPCR for identifying human ChREBPα/ß isoforms in hepatic and adipose tissues.

Most quantitative real-time PCR (qPCR) detection methods use two types of chemistries to measure the expression levels of ChREBP isoforms, hydrolysis probes for ChREBPα and SYBR Green for ChREBPß. Hydrolysis probes are not available to determine the ChREBPß isoform. The aim of this study was to develop a qPCR assay based only on hydrolysis probes for both ChREBP isoforms. Liver and adipose tissue biopsies from patients undergoing elective cholecystectomy surgery were used to perform qPCR. To validate this assay, the results were compared with sequencing and High Resolution Melting (HRM) PCR assays. Direct sequencing was used to determine the sequence showing site where ChREBPß presents its specific splicing (1 b exon/2 exon) in order to design the primers and the probe. We developed a qPCR assay to determine the ChREBP isoforms expression based on hydrolysis probes. It assays showed good efficiency (95.50%, on average), high reproducibility, and a strong linear correlation (R2 ≥ 0.99) for tissues tested. HRM analysis confirmed the specificity of the primers and the result of this assay matched (100%) with the outcomes obtained by sequencing and qPCR. Also, we obtained the ChREBPß sequence showing exon 1b spliced to exon 2, bypassing exon 1a, and retaining the remainder of the ChREBPα exons. Based on the use of hydrolysis probes, our method can efficiently identify the expression of both ChREBP isoforms. Thus, the comparability of the qPCR results using a single chemistry (hydrolysis probes) to discriminate between both ChREBP isoforms was possible.

Asociación de los polimorfismos -319 C/T y +49 A/G del gen CTLA-4 en pacientes con infección por el virus de la hepatitis C / Association of -319 C/T and +49 A/G polymorphisms of CTLA-4gene in patients with hepatitis C virus infection

Introducción y objetivo: Cambios moleculares en el gen CTLA-4 pueden modificar la habilidad para controlar la proliferación de los linfocitos T, y promover la persistencia o eliminación del virus de la hepatitis C (VHC). Nuestro objetivo fue investigar la frecuencia y asociación de los polimorfismos −319 C/T y +49 A/G del gen CTLA-4, en pacientes con infección por VHC. Métodos: Los polimorfismos del gen CTLA-4 (−319 C/T en la región promotora y +49 A/G en el exón 1) fueron analizados por T-ARMS-PCR en 420 individuos, incluidos 205 pacientes con infección crónica por VHC y 215 sujetos sanos. Resultados: Se encontró una asociación positiva del alelo +49G con la infección por VHC (OR 1,48; IC 95% 1,09-2,02; p=0,02), y con el sexo masculino (OR 1,80; IC 95% 1,16-2,79; p=0,02), ambos en enfermedad crónica (sin cirrosis). Se observaron diferencias significativas en la distribución de los genotipos del polimorfismo +49 A/G, entre los pacientes con infección por VHC y los sujetos sanos en un modelo genético dominante (GG+GA frente a AA; OR1,57; IC 95% 1,05-2,33; p=0,04). No se observaron diferencias en las frecuencias del polimorfismo −319 C/T, entre pacientes con VHC y sujetos sanos. El haplotipo -319C/+49G confiere susceptibilidad a la infección por el genotipo 3 del VHC (OR 10,68; IC 95% 1,17-96,97; p=0,04). Conclusiones: El alelo +49G confiere susceptibilidad a infección por VHC y a infección en el sexo masculino, ambos en enfermedad crónica. Además, el haplotipo -319C/+49G confiere susceptibilidad a la infección por el genotipo 3 del VHC. Nuestros resultados evidencian una implicación importante de los polimorfismos −319 C/T y +49 A/G en la infección por VHC

Introduction and objective: Molecular changes in the CTLA-4 gene can modify the ability to control T lymphocyte proliferation, and promote the persistence or elimination of the hepatitis C virus (HCV). We aimed to investigate the frequency and association of -319 C/T and +49 A/G polymorphism in the CTLA-4 gene in patients infected with HCV. Methods: The CTLA-4 gene polymorphisms (-319 C/T in the promoter region, and +49 A/G in exon 1) were analysed by T-ARMS-PCR in 420 individuals, including 205 chronic HCV infected patients and 215 healthy subjects. Results: We found a positive association of +49G allele with HCV infection (OR 1.48; 95% CI 1.09-2.02; p=.02), and with males (OR 1.80; 95% CI 1.16-2.79; p=.02), both in chronic disease (without cirrhosis). Also, significant differences in +49 A/G genotypes distribution between HCV infected patients and healthy subjects were shown in a dominant genetic model (GG+GA versus AA; OR 1.57; 95% CI 1.05-2.33; p=.04). No significant differences were observed in the -319 C/T polymorphism between HCV infected patients and healthy subjects. Moreover, -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection (OR 10.68; 95% CI 1.17-96.97; p=.04). Conclusions: The +49G allele confers susceptibility to HCV infection and with male gender, both in chronic disease. In addition, the −319C/+49G haplotype confers susceptibility to HCV genotype 3 infection. Our results support an important role of the −319 C/T and +49 A/G polymorphisms in HCV infection

Association of -319 C/T and +49 A/G polymorphisms of CTLA-4 gene in patients with hepatitis C virus infection. / Asociación de los polimorfismos −319 C/T y +49 A/G del gen CTLA-4 en pacientes con infección por el virus de la hepatitis C.

INTRODUCTION AND OBJECTIVE: Molecular changes in the CTLA-4 gene can modify the ability to control T lymphocyte proliferation, and promote the persistence or elimination of the hepatitis C virus (HCV). We aimed to investigate the frequency and association of -319 C/T and +49 A/G polymorphism in the CTLA-4 gene in patients infected with HCV. METHODS: The CTLA-4 gene polymorphisms (-319 C/T in the promoter region, and +49 A/G in exon 1) were analysed by T-ARMS-PCR in 420 individuals, including 205 chronic HCV infected patients and 215 healthy subjects. RESULTS: We found a positive association of +49G allele with HCV infection (OR 1.48; 95% CI 1.09-2.02; p=.02), and with males (OR 1.80; 95% CI 1.16-2.79; p=.02), both in chronic disease (without cirrhosis). Also, significant differences in +49 A/G genotypes distribution between HCV infected patients and healthy subjects were shown in a dominant genetic model (GG+GA versus AA; OR 1.57; 95% CI 1.05-2.33; p=.04). No significant differences were observed in the -319 C/T polymorphism between HCV infected patients and healthy subjects. Moreover, -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection (OR 10.68; 95% CI 1.17-96.97; p=.04). CONCLUSIONS: The +49G allele confers susceptibility to HCV infection and with male gender, both in chronic disease. In addition, the -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection. Our results support an important role of the -319 C/T and +49 A/G polymorphisms in HCV infection.

Mechanisms of action of acetaldehyde in the up-regulation of the human α2(I) collagen gene in hepatic stellate cells: key roles of Ski, SMAD3, SMAD4, and SMAD7.

Alcohol-induced liver fibrosis and eventually cirrhosis is a leading cause of death. Acetaldehyde, the first metabolite of ethanol, up-regulates expression of the human α2(I) collagen gene (COL1A2). Early acetaldehyde-mediated effects involve phosphorylation and nuclear translocation of SMAD3/4-containing complexes that bind to COL1A2 promoter to induce fibrogenesis. We used human and mouse hepatic stellate cells to elucidate the mechanisms whereby acetaldehyde up-regulates COL1A2 by modulating the role of Ski and the expression of SMADs 3, 4, and 7. Acetaldehyde induced up-regulation of COL1A2 by 3.5-fold, with concomitant increases in the mRNA (threefold) and protein (4.2- and 3.5-fold) levels of SMAD3 and SMAD4, respectively. It also caused a 60% decrease in SMAD7 expression. Ski, a member of the Ski/Sno oncogene family, is colocalized in the nucleus with SMAD4. Acetaldehyde induces translocation of Ski and SMAD4 to the cytoplasm, where Ski undergoes proteasomal degradation, as confirmed by the ability of the proteasomal inhibitor lactacystin to blunt up-regulation of acetaldehyde-dependent COL1A2, but not of the nonspecific fibronectin gene (FN1). We conclude that acetaldehyde up-regulates COL1A2 by enhancing expression of the transactivators SMAD3 and SMAD4 while inhibiting the repressor SMAD7, along with promoting Ski translocation from the nucleus to cytoplasm. We speculate that drugs that prevent proteasomal degradation of repressors targeting COL1A2 may have antifibrogenic properties.

TGF-ß1 up-regulates the expression of PDGF-ß receptor mRNA and induces a delayed PI3K-, AKT-, and p70(S6K) -dependent proliferative response in activated hepatic stellate cells.

BACKGROUND: Transforming growth factor beta 1 (TGF-ß1) is a pleiotropic cytokine that activates hepatic stellate cell (HSC) proliferation, but inhibits parenchymal cell proliferation. Therefore, we hypothesize that TGF-ß1 regulates HSC proliferation and elucidated its molecular action. METHODS: In order to elucidate the molecular mechanism whereby TGF-ß1 up-regulates platelet derived growth factor beta (PDGF-ß) receptor mRNA and induces a delayed proliferation of HSC, we used proliferation and apoptosis assays as well as RT-PCR, Western blot analysis, immunostaining, and flow cytometry in mouse and rat HSC. RESULTS: We show that TGF-ß1 markedly induces the proliferation of mouse HSC in culture with concomitant 2.1-fold (p < 0.001) stimulation in [(3) H]-thymidine incorporation into cellular DNA. This induction is maximal between 24 and 36 hours postcytokine exposure that is triggered by 7.6-fold (p < 0.001) up-regulation of PDGF-ß receptor mRNA and associated increase in PDGF-ß receptor protein after 48 hours. TGF-ß1-dependent HSC proliferation is mimicked by H2 O2 that is inhibited by catalase, implying that TGF-ß1 action is mediated via reactive oxygen species. HSC proliferation is blunted by PDGF-ß receptor-neutralizing antibody as well as by specific inhibitors of PI3 kinase (PI3K), AKT, and p70(S6K) , indicating that the action of TGF-ß1 involves the activation of PDGF-ß receptor via the PI3K/AKT/p70(S6K) signaling pathway. TGF-ß1 also induces a reorganization of actin and myosin filaments and cell morphology leading to the formation of palisades although their myosin and actin contents remained constant. These findings suggest that TGF-ß1-mediated oxidative stress causes the transdifferentiation of HSC and primes them for extracellular matrix (ECM) deposition and scar contraction. CONCLUSIONS: We conclude that liver injury up-regulates TGF-ß1 that inhibits parenchymal cell proliferation, but stimulates HSC proliferation leading to the production of ECM and type I collagen resulting in fibrosis.

Fibrogenic actions of acetaldehyde are ß-catenin dependent but Wingless independent: a critical role of nucleoredoxin and reactive oxygen species in human hepatic stellate cells.

We investigated whether the fibrogenic actions of acetaldehyde, the immediate oxidation product of ethanol, are mediated via Wingless (WNT) and/or ß-catenin pathways in human hepatic stellate cells (HSC). First, we show that both ß-catenin small inhibitory RNA and a dominant negative-MYC expression vector markedly down-regulated the expressions of fibrogenic genes in freshly isolated HSC. We further show that acetaldehyde up-regulated platelet-derived growth factor receptor beta mRNA and protein expressions ranging from 4.0- to 7.2-fold (P<0.001). Acetaldehyde induced MYC and collagen type-1 alpha-2 mRNA and protein expressions were WNT independent because DKK1, an antagonist of the canonical WNT/ß-catenin pathway, completely failed to block these inductions. Acetaldehyde increased phospho-glycogen synthase kinase-3 beta (GSK3B) protein by 31% (P<0.01), whereas phospho-ß-catenin protein decreased by 50% (P ≤ 0.01). Significantly, in contrast to 43% (P<0.01) inhibition of ß-catenin nuclear translocation in nucleoredoxin (NXN)-overexpressed HSC, acetaldehyde profoundly stimulated ß-catenin nuclear translocation by 51%, (P<0.01). Acetaldehyde also increased the cellular reactive oxygen species level 2-fold (P<0.001) with a concomitant 2-fold (P<0.001) increase in 4-hydroxynonenal adducts. Conversely, there was a 44% decrease (P<0.001) in glutathione levels with a concomitant 76% (P<0.001) decrease in the level of NXN/ disheveled (DVL) complex. Based on these findings, we conclude that actions of acetaldehyde are mediated by a mechanism that inactivates NXN by releasing DVL, leading to the inactivation of GSK3B, and thereby blocks ß-catenin phosphorylation and degradation. Thus, the stabilized ß-catenin translocates to the nucleus where it up-regulates the fibrogenic pathway genes. This novel mechanism of action of acetaldehyde has the potential for therapeutic interventions in liver fibrosis induced by alcohol.

Effect of Ala54Thr polymorphism of FABP2 on anthropometric and biochemical variables in response to a moderate-fat diet.

OBJECTIVE: To analyze the effect of the fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism on anthropometric and biochemical variables in response to a moderate-fat diet in overweight or obese subjects. METHODS: One hundred nine subjects with a body mass index ≥ 25 kg/m(2) were studied. Participants underwent a dietary intervention that consisted of 30% fat (saturated fat <7% of total calories), 15% protein, and 55% carbohydrates. The FABP2 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Anthropometric and biochemical data were measured at baseline, 1 mo, and 2 mo of nutritional intervention. RESULTS: The mean age was 38.6 ± 11.3 y and the mean body mass index 32.7 ± 6.1 kg/m(2), with 20 men (18%) and 89 women (82%). Fifty-three patients (48.6%) had genotype Ala54Ala (wild-type group) and 56 patients had genotype Ala54Thr/Thr54Thr (51.4%, mutant group). At baseline, no significant difference was found between the FABP2 genotypes groups, except for the carbohydrate intake and resting metabolic rate, which were higher in the Ala54Thr/Thr54Thr group (P < 0.05). At 2 mo, participants had lost 6.8% of their initial weight. The Ala54Thr/Thr54Thr group compared with the Ala54Ala group showed significant decreases in the parameters of weight (-7.5 versus -4.2 kg), body mass index (-2.1 versus -1.2 kg/m(2)), waist circumference (-7.6 versus -5.2 cm), waist-to-hip ratio (-0.04 versus -0.02), and C-reactive protein (-1.4 versus -0.76 mg/L), respectively (P < 0.05). After the resting metabolic rate was adjusted, the decreases in waist circumference, waist-to-hip ratio, and C-reactive protein remained significant between the two groups. CONCLUSIONS: This study showed that the Thr54 allele carriers responded better to a moderate-fat diet.

Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients

A high prevalence of occult hepatitis B (OHB) genotype H infections has been observed in the native Mexican Nahua population. In addition, a low incidence of hepatitis B virus (HBV)-associated hepatocellular carcinoma has been described in Mexico. The immune response to infection among OHB-infected patients has been poorly evaluated in vivo. Therefore, we assessed the expression profiles of 23 cytokines in OHB genotype H-infected Nahua patients. A total of 41 sera samples from natives of the Nahua community were retrospectively analysed. Based on their HBV antibody profiles, patients were stratified into two groups: OHB patients (n = 21) and patients that had recovered from HBV infection (n = 20). Herein, we report distinctive cytokines profiles in OHB-infected individuals. Compared to healthy controls (n = 20) and patients who resolved HBV infection, OHB-infected patients displayed an increase in interleukin (IL)-2 secretion in addition to a characteristic inflammation profile (decrease in IL-8 and tumour necrosis factor-alpha levels and increased levels of tumour growth factor-beta). IL-15 and interferon-gamma levels were reduced in OHB-infected individuals when compared to those patients who resolved HBV infection. In contrast, OHB patients showed an increase in monocyte chemoattractant protein (MCP)-1 and MCP-2 compared to healthy controls and patients who resolved HBV infection. These findings suggest that cytokine expression can influence the severity of OHB disease and could lead to new investigation into the treatment of liver and other infectious diseases.

The role of dystroglycan in PDGF-BB-dependent migration of activated hepatic stellate cells/myofibroblasts.

Hepatic stellate cells are embedded in the loose connective tissue matrix within the space of Disse. This extracellular matrix contains several basement membrane components including laminin, but its composition changes during liver injury because of the production of extracellular matrix components found in scar tissue. These changes in extracellular matrix composition and in cell-extracellular matrix interactions may play a key role in hepatic stellate cell transdifferentiation. In this communication we used early passages of mouse hepatic stellate cells (activated HSC/myofibroblasts) to study the platelet-derived growth factor BB (PDGF-BB)-dependent expression and regulation of ß-dystroglycan and its role in activated HSC/myofibroblast migration. We used Northern and Western analysis to study dystroglycan expression and confocal microscopy to investigate changes in subcellular distribution of the protein. Activated HSC migration was investigated using an in vitro wound-healing assay. PDGF-BB induced significant changes in dystroglycan regulation and subcellular distribution of the protein. Whereas steady-state levels of dystroglycan mRNA remained constant, PDGF-BB increased dystroglycan transcription but shortened the t(1/2) by 50%. Moreover, PDGF-BB changed dystroglycan and α5-integrin cellular distribution. Cell migration experiments revealed that PDGF-BB-dependent migration of activated HSC/myofibroblasts was completely blocked by neutralizing antibodies to fibronectin, α5-integrin, laminin, and ß-dystroglycan. Overall, these findings suggest that both laminin and fibronectin and their receptors play a key role in PDGF-BB-induced activated HSC migration.

Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients.

A high prevalence of occult hepatitis B (OHB) genotype H infections has been observed in the native Mexican Nahua population. In addition, a low incidence of hepatitis B virus (HBV)-associated hepatocellular carcinoma has been described in Mexico. The immune response to infection among OHB-infected patients has been poorly evaluated in vivo. Therefore, we assessed the expression profiles of 23 cytokines in OHB genotype H-infected Nahua patients. A total of 41 sera samples from natives of the Nahua community were retrospectively analysed. Based on their HBV antibody profiles, patients were stratified into two groups: OHB patients (n = 21) and patients that had recovered from HBV infection (n = 20). Herein, we report distinctive cytokines profiles in OHB-infected individuals. Compared to healthy controls (n = 20) and patients who resolved HBV infection, OHB-infected patients displayed an increase in interleukin (IL)-2 secretion in addition to a characteristic inflammation profile (decrease in IL-8 and tumour necrosis factor-alpha levels and increased levels of tumour growth factor-beta). IL-15 and interferon-gamma levels were reduced in OHB-infected individuals when compared to those patients who resolved HBV infection. In contrast, OHB patients showed an increase in monocyte chemoattractant protein (MCP)-1 and MCP-2 compared to healthy controls and patients who resolved HBV infection. These findings suggest that cytokine expression can influence the severity of OHB disease and could lead to new investigation into the treatment of liver and other infectious diseases.

Molecular epidemiology of hepatitis C virus genotypes in west Mexico.

The identification of hepatitis C virus (HCV) genotypes and subtypes may be helpful to identify the source of an HCV outbreak among a specific group of individuals within a given country or the pattern of spread throughout nations worldwide. Mexico is a transit country for people who migrate north towards the United States from Central and South America, however, to date, no Mexican HCV sequences have been reported. The present study was conducted to identify the HCV genotypes and subtypes prevalent in Mexico by DNA sequencing and phylogenetic analysis in the NS5B region of the HCV genome. Serum samples from a total of 75 anti-HCV positive patients were included in this study. Out of the 75 samples, 48 cases (64%) were amplifiable in the 5' UTR and 46 (61%) in NS5B region. HCV genotype 1a determined in 54.3% (25/46) was predominant in this cohort, followed by 1b 21.8% (10/46), 2b 13% (6/46), 3a 6.5% (3/46), and 2a 4.4% (2/46). Phylogenetic analysis showed that HCV sequences of genotype 1 (1a and 1b) were clustering more closely to the United States isolates published previously. These results may suggest that both Mexico and the United States share an epidemiological network of HCV genotype 1 while other genotypes represent sporadic infections that are specific to Mexico.

A low steady HBsAg seroprevalence is associated with a low incidence of HBV-related liver cirrhosis and hepatocellular carcinoma in Mexico: a systematic review.

To address the relationship between hepatitis B virus (HBV) endemicity and HBV-related liver diseases in Mexico. Research literature reporting on HBsAg and antibody to hepatitis B core antigen (anti-HBc) prevalence in Mexican study groups were searched in NLM Gateway, PubMed, IMBIOMED, and others. Weighted mean prevalence (WMP) was calculated from the results of each study group. A total of 50 studies were analyzed. Three nationwide surveys revealed an HBsAg seroprevalence of less than 0.3%. Horizontal transmission of HBV infection occurred mainly by sexual activity and exposure to both contaminated surgical equipment and body fluids. High-risk groups exposed to these factors included healthcare workers, pregnant women, female sex workers, hemodialysis patients, and emergency department attendees with an HBsAg WMP ranging from 1.05% (95% confidence interval [CI], 0.68-1.43) to 14.3% (95% CI, 9.5-19.1). A higher prevalence of anti-HBc in adults than those younger than 20 years was associated with the main risk factors. Anti-HBc WMP ranged from 3.13% (95% CI, 3.01-3.24) in blood donors to 27.7% (95% CI, 21.6-33.9) in hemodialysis patients. A heterogeneous distribution of HBV infection was detected, mainly in native Mexican groups with a high anti-HBc WMP of 42.0% (95% CI, 39.5-44.3) but with a low HBsAg WMP of 2.9% (95% CI 2.08-3.75). Estimations of the Mexican population growth rate and main risk factors suggest that HBsAg seroprevalence has remained steady since 1974. A low HBsAg prevalence is related to the low incidence of HBV-related liver cirrhosis and hepatocellular carcinoma (HCC) previously reported in Mexico.

Association of the epsilon 2 allele of APOE gene to hypertriglyceridemia and to early-onset alcoholic cirrhosis.

BACKGROUND: The diverse incidence of alcoholic cirrhosis around the world and the fact that not all alcoholic drinkers develop liver disease indicates that genetic and environmental factors play an important role in the development of liver cirrhosis. Lipids participate in early stages of alcoholic cirrhosis. Therefore variations in the plasma lipid profile due to primary (genetic) or secondary (environmental) dyslipidemia could affect the development of liver disease. The aim of this study was to analyze the lipid profile and apolipoprotein E (APOE) polymorphism in patients with alcoholic liver cirrhosis (AC) and determine the risk associated with genotype polymorphism with the onset of alcoholic cirrhosis. METHODS: In a case and control study, 86 patients with AC divided into hyperlipidemic (H) and non-hyperlipidemic (non-H) groups, and 133 healthy individuals (C) matched by age and sex were studied. Lipid profile and liver function tests were measured by enzymatic methods. The APOE genotypes were identified by PCR-RFLP's. RESULTS: A statistically significant increase of the APOE*2 allele and genotypes 2/2, 2/3, and 2/4 was present in AC patients compared to C group. A hyperlipidemic state characterized by increased levels of triglycerides and apolipoprotein B (APOB) and a decrease of high density lipoprotein-cholesterol (HDL-c) was detected in young-aged patients (31.2 +/- 6.2 years old vs. 46.3 +/- 12.5 years old). In this group, hypertriglyceridemia was closely associated to APOE*2 allele and to an early onset of liver cirrhosis. By contrast, APOE*4 allele was associated with a longer duration of alcohol intake (>20 years) in the non-H group. CONCLUSIONS: This study shows the association of hypertriglyceridemia and APOE allele with the early onset of alcoholic liver cirrhosis, and the interaction between environmental factors, such as duration of alcohol abuse and amount of alcohol intake, and genetic factors (APOE*2 allele) on the hypertriglyceridemic process.