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Luca Valenti

Publications and source records attributed to Luca Valenti.

11 recordsLinked to original sources
PubMed2025

Interplay among lipoprotein(a), hepatic and vascular damage in individuals with metabolic dysfunction.

BACKGROUND: The relationship between plasma lipoprotein(a) [Lp(a)] levels and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. The aim of this study was to examine the combined effects of Lp(a) levels on liver and vascular damage. METHODS: The study was conducted using the Liver-Bible cohort of individuals with metabolic dysfunction (n = 859, 808 with genomic information) and the Milan Biobank (n = 6963). Genome-wide association studies (GWAS) and polygenic risk scores (PRS) were used to evaluate the inherited factors influencing plasma Lp(a) levels. RESULTS: In the Liver-Bible cohort, genetic variation in the LPA gene was the strongest determinant of Lp(a), followed by liver stiffness measurement (LSM). Additionally, circulating Lp(a) levels, but not genetic predisposition, were inversely related to LSM, suggesting that MASLD severity may affect Lp(a) secretion. Among participants with more severe insulin resistance (n = 250), Lp(a) levels (odds ratio 6.7, 95% CI 1.0-53.0, p = 0.046) and LSM (odds ratio 13.7, 95% CI 1.4-172.2, p = 0.023) were associated with greater prevalence of carotid atherosclerotic plaques, regardless of traditional cardiovascular risk factors. In the Milan Biobank, genetically predicted higher Lp(a) levels tended to increase the risk of liver-related outcomes, whereas genetically predicted MASLD was associated with lower circulating Lp(a) levels. CONCLUSIONS: The results of this study suggest that liver damage is more likely the cause of reduced plasma Lp(a) levels rather than a consequence. Assessing plasma Lp(a) levels and the extent of liver damage could improve the prediction of vascular damage.

Humans↗
PubMed2006

Alpha 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage.

Hyperferritinemia, a common feature of nonalcoholic fatty liver disease (NAFLD), has been associated with steatohepatitis and fibrosis. Heterozygosity for alpha 1-antitrypsin (AAT) mutations is a cofactor of liver damage, and AAT influences inflammation and iron metabolism. This study evaluated the prevalence of the common AAT PiS/PiZ mutants in 353 patients with NAFLD, 195 of whom had hyperferritinemia, versus 114 matched controls and their influence on iron metabolism and the severity of liver damage in the 212 patients submitted to biopsy. PiS and PiZ alleles were searched for by restriction analysis. Thirty-eight patients (10.8%) carried non-MM genotypes versus 4/114 (3.5%) controls (P = .02). Patients carrying AAT mutations had higher ferritin (573 [454-966] vs. 348 [201-648]; P = .001) with similar transferrin saturation. The difference was more evident in males (P < .0001) and significant in patients not carrying HFE genotypes associated with iron overload (P = .015). The prevalence of non-MM genotypes was higher in patients with hyperferritinemia than in those without (28/195, 14% vs. 10/158, 6%, P = .016), and AAT mutations were associated with higher prevalence of sinusoidal siderosis (17/27, 63% vs. 70/180, 39%; P = .02), and sinusoidal/total iron score (46.3 +/- 38% vs. 25.1 +/- 35%, P = .01). Although ferritin was independently associated with fibrosis (P = .047), AAT mutations favoring sinusoidal iron deposition did not affect liver damage. In conclusion, AAT mutations are associated with hyperferritinemia and sinusoidal iron accumulation, but not with more severe liver damage in NAFLD.

Alleles↗
PubMed2005

TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis.

BACKGROUND/AIMS: TNFalpha induces insulin resistance and promoter polymorphisms of TNFalpha gene affect the release of this cytokine, implicated in the pathogenesis of HCV-related diabetes and fatty liver. The aim was to define whether in patients with HCV chronic hepatitis TNFalpha genotype influences TNFalpha activity, insulin resistance, and the severity of the disease. METHODS: 186 patients, 65% with steatosis, 17% with diabetes. TNFalpha and sTNFR2 were determined by ELISA, insulin resistance by HOMA-R index and TNFalpha -238, -308, and -863 polymorphisms by restriction analysis. RESULTS: TNFalpha, sTNFR2, and insulin resistance were higher in patients than in 89 controls. TNFalpha pathway activity was correlated with LDL cholesterol, steatosis, and insulin resistance, which, in turn, was correlated with the severity of liver damage. Patients subdivided according to TNFalpha genotype significantly differed for TNFalpha release, insulin sensitivity and the prevalence of cirrhosis. The -308 and -238 TNFalpha polymorphisms, characterized by increased promoter activity, were associated with higher TNFalpha activity, insulin resistance and severity of the disease, whereas the -863 polymorphism, characterized by reduced promoter activity, with lower TNFalpha activity, and higher insulin sensitivity. CONCLUSIONS: TNFalpha genotype modulates the activity of the TNFalpha pathway, influences insulin sensitivity and the severity of HCV chronic hepatitis.

Adult↗
PubMed2005

Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes.

Activation of NAD-dependent deacetylases, or Sirtuins, prolongs life span and mimics the effects of caloric restriction in yeast. The FoxO subfamily of forkhead transcription factors has been shown to mediate some of the effects of Sirtuins. Here we have shown that Sirtuin activation or hydrogen peroxide treatment overrides the phosphorylation-dependent nuclear exclusion of FoxO1 caused by growth factors and causes nuclear translocation of FoxO1 in hepatocytes. Kinetic measurements of nuclear fluorescence recovery after photobleaching show that FoxO1 is readily diffusible within the nucleus under normal conditions but becomes restricted within a nuclear subdomain following treatment with the prototypical Sirtuin agonist resveratrol or oxidative stress. Expression of FoxO1 target genes is accordingly increased, leading to activation of gluconeogenesis and increased glucose release from hepatocytes. Selective modulation of the FoxO/Sirtuin interaction represents a promising therapeutic modality for metabolic disorders.

Acetylation↗
PubMed2004

Treatment choices for people infected with HCV.

Hepatitis C virus (HCV) infection is one of the leading causes of liver disease in the world. It is a common cause of cirrhosis and hepatocellular carcinoma (HCC), as well as the most common reason for liver transplantation. Thus, appropriate therapeutic approaches have a strong clinical impact on the morbidity and mortality of HCV-infected patients. In this review we outline the most recent results in the therapy of HCV chronic hepatitis. Patients with the best prognostic factors treated with combination therapy (peginterferon and ribavirin) obtained a sustained response rate of 80-95%. We also provide some hints on the most promising results of the newest therapeutic options, which include molecules that inhibit specific enzymes, such as inhibitors of serine proteases, which are now in preclinical or early phase human trials. Host factors influencing the rate of response are also outlined.

Acute Disease↗
PubMed2004

TNFalpha promoter polymorphisms.

Polymorphisms in the promoter of the tumor necrosis factor alpha (TNFalpha) gene have been reported to affect the transcription rate and the release of this cytokine. Among the best studied, the -238 and -308 polymorphisms have been associated with an increased transcriptional activity and TNFalpha release, whereas the -863 polymorphism have been associated with a reduced transcriptional activity. A growing body of evidence indicates that these polymorphisms may affect susceptibility to different diseases. Here we describe a method to detect the -238, -308, and -863 TNFalpha polymorphisms by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Briefly, DNA is amplified by PCR using mutagenic primers containing a single base-pair mismatch adjacent to the polymorphic site to introduce a restriction site into the wild-type nucleotide sequences after amplification. The PCR products are then digested with specific restriction enzymes and analyzed by agarose gel electrophoresis.

Alleles↗
PubMed2002

Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease, which can range from fatty liver alone to nonalcoholic steatohepatitis and cirrhosis, is related to insulin resistance. Tumor necrosis factor alpha (TNF-alpha) may induce insulin resistance, and polymorphisms of its promoter have been associated with an increased release of this cytokine. We analyzed (1) the prevalence of insulin resistance, (2) the prevalence of the 238 and 308 TNF-alpha polymorphisms, and (3) the relationship among TNF-alpha polymorphisms, insulin resistance, and the occurrence of steatohepatitis in 99 patients with nonalcoholic fatty liver diagnosed by ultrasonography and confirmed by histologic analysis in the 53 who underwent biopsy. METHODS: Insulin resistance was evaluated by the homeostatic metabolic assessment insulin resistance indices and TNF-alpha polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Insulin resistance was detected in almost all of the patients and was more severe in those with steatohepatitis. The prevalence of the 238, but not of the 308, TNF-alpha polymorphism was higher in subjects with nonalcoholic fatty liver than in controls (31% vs. 15%; P < 0.0001), and patients positive for TNF-alpha polymorphisms had higher insulin resistance indices, a higher prevalence of impaired glucose tolerance, and a lower number of associated risk factors for steatosis. CONCLUSIONS: TNF-alpha polymorphisms could represent a susceptibility genotype for insulin resistance, nonalcoholic fatty liver, and steatohepatitis.

Adult↗
PubMedDate not supplied

Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are strong and independent risk factors for hepatocellular carcinoma (HCC) development. Patients with hereditary hemochromatosis (HH) are considered at risk of developing cancer. However, the interaction between HFE gene mutations and hepatitis viruses for HCC development has not been systematically searched for. To assess the interaction between HFE gene mutations and exogenous risk factors in the risk of HCC occurrence, a case-only approach, in which just a series of patients is enrolled, was used. Three hundred three cirrhotic patients (231 males, 72 females) from five liver units in different geographic areas of Italy, who developed HCC during regular follow-up between January 1999 and March 2003, and whose blood DNA was available, were analyzed. In all subjects, hepatitis B surface antigen (HBsAg), anti-HCV and HFE gene mutations were assayed; alcohol intake was recorded by history. The interaction between HFE genotypes and hepatitis viruses for HCC was estimated by multivariate analysis adjusting for the confounding effect of alcohol intake, area of residence and months of follow-up. Of the 303 HCC cases, 12 (4.0%) were heterozygous for the C282Y mutation, 93 (30.7%) for the H63D, and 198 (65.3%) homozygous for the wild allele. Multivariate analysis showed that C282Y heterozygous males were 3.8-fold (95% CI=1.0-15.2) more likely to be HBV positive and that H63D heterozygous females were 6.0-fold (95% CI=1.2-113.8) more likely to be HCV positive than wild type subjects. In conclusion, given the association between C282Y mutation and HBV infection in male patients with HCC, a careful evaluation and follow-up should be considered in the C282Y-positive subjects with hepatitis B virus related liver disease. The interaction between the H63D mutation and HCV, observed only in women, may reflect a higher sensitivity to H63D-induced iron metabolism abnormalities and a reduced antioxidant capability in the presence of an even minor increase of iron which may occur as a consequence of the coexistence of hepatitis C infection and heterozygosity for HH.

Antibodies, Viral↗
PubMedDate not supplied

Cytotoxic T-lymphocyte antigen-4 A49G polymorphism is associated with susceptibility to and severity of alcoholic liver disease in Italian patients.

AIMS: To determine whether the functional A49G polymorphism of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a T-cell surface molecule that modulates T-lymphocyte activation and influences the risk of developing alcohol-induced autoantibodies, plays a role in susceptibility to alcoholic liver disease (ALD) and influences disease severity in Italian alcohol abusers. METHODS: One hundred and eighty-three patients with chronic ALD (61 cirrhosis), 115 end-stage HCV cirrhosis, 102 non-alcoholic fatty liver disease (NAFLD), 93 healthy subjects and 43 heavy drinkers without liver disease were studied. CTLA-4 gene polymorphism was analysed by restriction analysis. RESULTS: The frequency of the CTLA-4 polymorphism was higher in patients with ALD than in patients with HCV chronic hepatitis and NAFLD, healthy subjects (P < 0.0001), and heavy drinkers without liver disease (P = 0.02). In patients with ALD, homozygosity for the CTLA-4 polymorphic allele (G/G genotype) was more represented in subjects with cirrhosis (P = 0.047), and independently associated with the risk of cirrhosis (OR 3.5; P = 0.03). CONCLUSIONS: The CTLA-4 polymorphic G allele, probably by interfering with the immune response, may confer susceptibility to ALD and, in homozygous state, to alcoholic cirrhosis.

Adenine↗