Liver ChREBP deficiency inhibits fructose-induced insulin resistance in pregnant mice and female offspring.

High fructose intake during pregnancy increases insulin resistance (IR) and gestational diabetes mellitus (GDM) risk. IR during pregnancy primarily results from elevated hormone levels. We aim to determine the role of liver carbohydrate response element binding protein (ChREBP) in insulin sensitivity and lipid metabolism in pregnant mice and their offspring. Pregnant C57BL/6J wild-type mice and hepatocyte-specific ChREBP-deficient mice were fed with a high-fructose diet (HFrD) or normal chow diet (NC) pre-delivery. We found that the combination of HFrD with pregnancy excessively activates hepatic ChREBP, stimulating progesterone synthesis by increasing MTTP expression, which exacerbates IR. Increased progesterone levels upregulated hepatic ChREBP via the progesterone-PPARγ axis. Placental progesterone activated the progesterone-ChREBP loop in female offspring, contributing to IR and lipid accumulation. In normal dietary conditions, hepatic ChREBP modestly affected progesterone production and influenced IR during pregnancy. Our findings reveal the role of hepatic ChREBP in regulating insulin sensitivity and lipid homeostasis in both pregnant mice consuming an HFrD and female offspring, and suggest it as a potential target for managing gestational metabolic disorders, including GDM.

Triphenyl phosphate (TPP) exposure promotes proliferation and migration capabilities of gastric cancer cells: Insights from gene expression and pathway analysis.

BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Triphenyl phosphate (TPP) is a prevalent flame retardant, but its health implications remain to be thoroughly understood. OBJECTIVE: To explore the link between TPP exposure and gastric cancer by examining gene expression patterns and developing a predictive model. METHODS: Gene expression data were sourced from The Cancer Genome Atlas (TCGA) and the Comparative Toxicogenomics Database (CTD). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were employed for analysis. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to obtain phosphate flame retardant-related scores. A predictive model was constructed through differential analysis, univariate COX regression, and LASSO regression. Molecular docking was performed to assess protein interactions with TPP. RESULTS: ssGSEA identified scores related to phosphate flame retardants in gastric cancer, which had a strong association with immune-related traits. Several genes associated with TPP were identified and used to develop a prognostic model that has clinical significance. Molecular docking showed a high binding affinity of TPP with MTTP, a gene related to lipid metabolism. Pathway analysis indicated that TPP exposure contributes to gastric cancer through lipid metabolic processes. CONCLUSION: The study establishes a potential correlation between TPP exposure and gastric cancer onset, pinpointing key genes and pathways involved. This underscores the significance of environmental factors in gastric cancer research and presents a potential diagnostic tool for clinical application.

Low LDL Cholesterol Is Not an Independent Risk Factor for Hepatic Steatosis.

BACKGROUND: Genetic mutations causing defective VLDL secretion and low LDL cholesterol are associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). AIMS: Determine if low LDL cholesterol (< 5th percentile) was an independent predictor of hepatic steatosis. METHODS: Secondary data analysis of the Dallas Heart study (an urban, multiethnic, probability-based sample), we defined hepatic steatosis utilizing intrahepatic triglyceride (IHTG) analyzed using magnetic resonance spectroscopy in conjunction and available demographic, serological and genetic information. We exclude patients on lipid lowering medications. RESULTS: Of the 2094 subjects that met our exclusion criteria, 86 had a low LDL cholesterol, of whom 19 (22%) exhibited hepatic steatosis. After matching for age, sex, BMI, and alcohol consumption, low LDL cholesterol was not a risk factor for hepatic steatosis compared to those with normal (50-180 mg/dL) or high (> 180 mg/dL) LDL. When analyzed as a continuous variable, we observed lower IHTG in the low LDL group compared to the normal or high LDL groups (2.2%, 3.5%, 4.6%; all pairwise comparisons p < 0.001). Subjects with both hepatic steatosis and low LDL cholesterol exhibited a more favorable lipid profile but similar insulin resistance and hepatic fibrosis risk compared to other subjects with hepatic steatosis. The distribution of variant alleles associated with NAFLD, including PNPLA3, GCKR, and MTTP was indistinguishable between subjects with hepatic steatosis and low versus high LDL cholesterol. CONCLUSION: These findings suggest that low serum LDL levels are not a useful predictor of hepatic steatosis and NAFLD. Moreover, subjects with low LDL exhibit a more favorable lipid profile and lower IHTG.

Association between MTTP genotype (-493G/T) polymorphism and hepatic steatosis in hepatitis C: a systematic review and meta-analysis.

BACKGROUND: Hepatitis C has been associated with the development of hepatic steatosis, which increases the risk of liver cancer. The microsomal triglyceride transporter protein (MTTP), is a lipid transport protein that mediates lipid metabolism and CD1d antigen presentation. The study aimed to explore the association between MTTP genotype (-493G/T) polymorphism and hepatic steatosis in hepatitis C. METHODS: The database "Pubmed, Cochrane library, CNKI, Web of science, Embase and CBM" were retrieved to identify the literature. The quality of the selected literature was evaluated using the "the Newcastle-Ottawa Scale" (NOS). Relevant data was extracted and analyzed using the Stata software. Heterogeneity was expressed by "Cochran's Q and I2", with I2 ≥ 50% or P < 0.05 indicating high heterogeneity. A random-effects model and subgroup analysis were conducted to identify the sources of heterogeneity. We also used "Funnel plots", "Egger's tests" and "Begg's tests" to evaluate biases in the literature. RESULTS: The study found a significant and positive association between liver steatosis and the HCV genotype 3 with a dominant model of the MTTP genotype (-493G/T) (OR = 11.57, 95%CI: 4.467-29.962, P < 0.001). In contrast, no correlation was found between hepatic steatosis and either the recessive, homozygous or heterozygous models (OR = 1.142, P = 0.5; OR = 1.581, P = 0.081; OR = 1.029, P = 0.86). There was no significant publication biases, as measured by the Funnel plot, and the Egger's and Begg's tests. Finally, sensitivity analysis showed the obtained results are stable. CONCLUSIONS: Dominant mutations in the T allele of the MTTP genotype (-493G/T) increase susceptibility to hepatic steatosis in patients presenting with the HCV genotype 3.

PRAP1 is a novel lipid-binding protein that promotes lipid absorption by facilitating MTTP-mediated lipid transport.

Microsomal triglyceride transfer protein (MTTP) is an endoplasmic reticulum resident protein that is essential for the assembly and secretion of triglyceride (TG)-rich, apoB-containing lipoproteins. Although the function and structure of mammalian MTTP have been extensively studied, how exactly MTTP transfers lipids to lipid acceptors and whether there are other biomolecules involved in MTTP-mediated lipid transport remain elusive. Here we identify a role in this process for the poorly characterized protein PRAP1. We report that PRAP1 and MTTP are partially colocalized in the endoplasmic reticulum. We observe that PRAP1 directly binds to TG and facilitates MTTP-mediated lipid transfer. A single amino acid mutation at position 85 (E85V) impairs PRAP1's ability to form a ternary complex with TG and MTTP, as well as impairs its ability to facilitate MTTP-mediated apoB-containing lipoprotein assembly and secretion, suggesting that the ternary complex formation is required for PRAP1 to facilitate MTTP-mediated lipid transport. PRAP1 is detectable in chylomicron/VLDL-rich plasma fractions, suggesting that MTTP recognizes PRAP1-bound TG as a cargo and transfers TG along with PRAP1 to lipid acceptors. Both PRAP1-deficient and E85V knock-in mutant mice fed a chow diet manifested an increase in the length of their small intestines, likely to compensate for challenges in absorbing lipid. Interestingly, both genetically modified mice gained significantly less body weight and fat mass when on high-fat diets compared with littermate controls and were prevented from hepatosteatosis. Together, this study provides evidence that PRAP1 plays an important role in MTTP-mediated lipid transport and lipid absorption.

A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases.

BACKGROUND: Our aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics of 100 cases reported in the literature. METHODS: We performed biochemical and molecular screenings in a Mexican girl with extremely low lipid levels and in her family. Further, we integrated and evaluated the characteristics of the cases with abetalipoproteinemia described in the literature. RESULTS: Our patient is a six-year-old girl who presented vomiting, chronic diarrhea, failure to thrive, malabsorption, acanthocytosis, anemia, transaminases elevation, and extremely low lipid levels. MTTP gene sequencing revealed homozygosity for a novel mutation p.Gly417Valfs*12 (G deletion c.1250). With the analysis of the reported cases, 60 clinical features (14 classical and 46 non-classical) were observed, being the most common acanthocytosis (57.5%), malabsorption (43.7%), and diarrhea (42.5%); 48.8% of the patients presented only classic clinical features, while the remaining 51.2% developed secondary effects due to a fat-soluble vitamin deficiency. An odds ratio analysis disclosed that patients diagnosed after 10 years of age have an increased risk for presenting clinical complications (OR = 18.0; 95% CI 6.0-54.1, p < 0.0001). A great diversity of mutations in MTTP has been observed (n = 76, being the most common p.G865X and p.N139_E140) and some of them with possible residual activity. CONCLUSION: The first Mexican patient with abetalipoproteinemia presents a novel MTTP mutation p.Gly417Valfs*12. Three factors that could modulate the phenotype in abetalipoproteinemia were identified: age at diagnosis, treatment, and the causal mutation.

"Mitotic Slippage" and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres.

Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.

Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia.

AIMS: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. MATERIALS AND METHODS: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. RESULTS: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. CONCLUSIONS: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.

Identification of antisense transcripts of the microsomal triglyceride transfer protein genes in humans and mice.

Microsomal triglyceride transfer protein (MTTP) is essential for the assembly and secretion of apoB-containing lipoproteins. Here, we report the presence of genes on the anti-sense strands of the human MTTP and mouse Mttp genes. The gene on the anti-sense strand of the human MTTP gene is called MTTP-AS1. It consists of 5 exons and 4 introns and codes for two different transcripts MTTP-AS1-Long and MTTP-AS1-Short. Exons 3 and 5 of the MTTP-AS1 gene are ancient and evolutionary conserved whereas exons 2 and 4 are primate specific. MTTP-AS1-Long is mainly in the liver and is in the cytoplasm of human hepatoma cells. MTTP-AS1-Short is in the testis. The MTTP-AS1-Long transcript shows complementarity with two different exons of the MTTP transcript. The gene on the opposite strand of the mouse Mttp gene is named as Mttpos. It consists of 2 exons and one intron and codes for one transcript. Partial sequence of the Mttpos exon 2 is homologous in several species from rodents to primates. Mttpos transcript is present in mouse liver, small intestine and testis. The Mttpos transcript shows significant complementarity with the corresponding mouse Mttp mRNA sequences. Further, we identified a conserved sequence in the human MTTP-AS1-Long and mouse Mttpos transcripts indicating for possible evolutionarily conserved regulatory function for these long noncoding RNAs. It is likely that these newly identified long noncoding RNAs interact with their complementary sequences in MTTP mRNAs and affect their stability or translation.

Severe riboflavin deficiency induces alterations in the hepatic proteome of starter Pekin ducks.

Suboptimal vitamin B2 status is encountered globally. Riboflavin deficiency depresses growth and results in a fatty liver. The underlying mechanisms remain to be established and an overview of molecular alterations is lacking. We investigated hepatic proteome changes induced by riboflavin deficiency to explain its effects on growth and hepatic lipid metabolism. In all, 360 1-d-old Pekin ducks were divided into three groups of 120 birds each, with twelve replicates and ten birds per replicate. For 21 d, the ducks were fed ad libitum a control diet (CAL), a riboflavin-deficient diet (RD) or were pair-fed with the control diet to the mean daily intake of the RD group (CPF). When comparing RD with CAL and CPF, growth depression, liver enlargement, liver lipid accumulation and enhanced liver SFA (C6 : 0, C12 : 0, C16 : 0, C18 : 0) were observed. In RD, thirty-two proteins were enhanced and thirty-one diminished (>1·5-fold) compared with CAL and CPF. Selected proteins were confirmed by Western blotting. The diminished proteins are mainly involved in fatty acid ß-oxidation and the mitochondrial electron transport chain (ETC), whereas the enhanced proteins are mainly involved in TAG and cholesterol biosynthesis. RD causes liver lipid accumulation and growth depression probably by impairing fatty acid ß-oxidation and ETC. These findings contribute to our understanding of the mechanisms of liver lipid metabolic disorders due to RD.

Genetic variation in the microsomal triglyceride transfer protein (-493G/T) is associated with hepatic steatosis in patients infected with hepatitis C virus.

BACKGROUND: In chronic hepatitis C, the fibrosis progression rates are extremely variable and can be influenced by factors associated with the host, virus and environment. Among the associated metabolic factors, hepatic steatosis is characterized by an accumulation of triglycerides in hepatocytes. In the host, genetic determinants of hepatic steatosis are observed, such as single-nucleotide polymorphisms (SNPs) in the microsomal triglyceride transfer protein (MTTP) gene. The MTTP -493G/T SNP appears to play an important role in the regulation of gene expression and influences the plasma concentration of circulating low-density lipoprotein (LDL). The present study investigated the influence of this SNP in the development of hepatic steatosis in patients with chronic hepatitis C and evaluated the association of hepatic steatosis with certain characteristics of these patients and the hepatitis C virus (HCV). METHODS: Two hundred thirty-nine patients with chronic hepatitis C were genotyped for the MTTP -493G/T SNP by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The association between hepatic steatosis and selected characteristics of the patient and virus was evaluated using bivariate and multivariate analyses. RESULTS: The most prevalent MTTP -493G/T genotype was GG (46%) followed by GT (43.5%) and TT (10.5%). Multivariate analysis of the total cohort revealed associations between the presence of hepatic steatosis and inflammatory activity of moderate to high intensity (P < 0.001), advanced age (P = 0.010), elevated gamma glutamyl transpeptidase (GGT) levels (P = 0.010) and low LDL levels (P = 0.022). Hepatic steatosis was also associated with the TT/GT genotype of the MTTP -493G/T SNP in patients infected with HCV genotype 3 (P < 0.001). CONCLUSIONS: In chronic hepatitis C patients infected with HCV genotype 3 and with the TT/GT genotype of the MTTP -493G/T SNP, a significant increase in hepatic steatosis was observed, which may indicate that this SNP has a significant influence on the accumulation of triglycerides in hepatocytes. Furthermore, associations were observed between hepatic steatosis and inflammatory activity of moderate to high intensity, advanced age, elevated GGT and low LDL levels.

The role of rumen-protected choline in hepatic function and performance of transition dairy cows.

High-producing dairy cows enter a period of negative energy balance during the first weeks of lactation. Energy intake is usually sufficient to cover the increase in energy requirements for fetal growth during the period before calving, but meeting the demand for energy is often difficult during the early stages of lactation. A catabolic state predominates during the transition period, leading to the mobilisation of energy reserves (NEFA and amino acids) that are utilised mainly by the liver and muscle. Increased uptake of mobilised NEFA by the liver, combined with the limited capacity of hepatocytes to either oxidise fatty acids for energy or to incorporate esterified fatty acids into VLDL results in fatty liver syndrome and ketosis. This metabolic disturbance can affect the general health, and it causes economic losses. Different nutritional strategies have been used to restrict negative effects associated with the energy challenge in transition cows. The provision of choline in the form of rumen-protected choline (RPC) can potentially improve liver function by increasing VLDL exportation from the liver. RPC increases gene expression of microsomal TAG transfer protein and APOB100 that are required for VLDL synthesis and secretion. Studies with RPC have looked at gene expression, metabolic hormones, metabolite profiles, milk production and postpartum reproduction. A reduction in liver fat and enhanced milk production has been observed with RPC supplementation. However, the effects of RPC on health and reproduction are equivocal, which could reflect the lack of sufficient dose-response studies.

Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities. METHODS: We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands. RESULTS: ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations. CONCLUSIONS: Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.

Prenatal ethanol exposure programs an increased susceptibility of non-alcoholic fatty liver disease in female adult offspring rats.

Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to high-fat diet (HFD)-induced NAFLD and its intrauterine programming mechanisms in female rat offspring with PEE. Rat model of intrauterine growth retardation (IUGR) was established by PEE, the female fetus and adult offspring that fed normal diet (ND) or HFD were sacrificed. The results showed that, in PEE+ND group, serum corticosterone (CORT) slightly decreased and insulin-like growth factor-1 (IGF-1) and glucose increased with partial catch-up growth; In PEE+HFD group, serum CORT decreased, while serum IGF-1, glucose and triglyceride (TG) increased, with notable catch-up growth, higher metabolic status and NAFLD formation. Enhanced liver expression of the IGF-1 pathway, gluconeogenesis, and lipid synthesis as well as reduced expression of lipid output were accompanied in PEE+HFD group. In PEE fetus, serum CORT increased while IGF-1 decreased, with low body weight, hyperglycemia, and hepatocyte ultrastructural changes. Hepatic IGF-1 expression as well as lipid output was down-regulated, while lipid synthesis significantly increased. Based on these findings, we propose a "two-programming" hypothesis for an increased susceptibility to HFD-induced NAFLD in female offspring of PEE. That is, the intrauterine programming of liver glucose and lipid metabolic function is "the first programming", and postnatal adaptive catch-up growth triggered by intrauterine programming of GC-IGF1 axis acts as "the second programming".

MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population.

BACKGROUND: The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (ApoB)-containing lipoproteins from the liver and intestine. Previous studies showed that functional polymorphisms in the MTTP gene correspond to lower LDL levels and protect against other traits of the metabolic syndrome. AIMS: Here, we aimed to investigate whether MTTP single nucleotide polymorphisms (SNPs) and their predicted haplotypes of linkage disequilibrium blocks contribute to non-alcoholic fatty liver disease (NAFLD) susceptibility in a Han Chinese population. METHODS: Seven tag SNPs in the MTTP gene were selected and genotyped in a frequency-matched case-control study in a population from Fuzhou City, China. We enrolled 580 patients with NAFLD and 580 healthy controls. RESULTS: In the multivariate logistic regression analysis, the rs1800804 (-164 T/C) was associated with an increased risk of NAFLD, while the rs1057613 A/G and rs3805335 C/T SNPs were associated with a decreased risk of NAFLD. The cumulative effect of the rs1800804 (-164 T/C), rs1057613 and rs3805335 was estimated, and a significant increased trend in the risk of NAFLD with increasing genetic risk score was observed (adjusted P(trend) = 0.014). Furthermore, the results of haplotype analysis suggested that the haplotype GC in block 1 containing the -164 C allele was associated with an increased risk of NAFLD, while haplotype TGTTC in block 2 was associated with a decreased risk of NAFLD. CONCLUSIONS: Our data show that MTTP genetic polymorphisms influence the susceptibility to developing NAFLD independently or jointly in the Han Chinese population.

Hypoxia-inducible lipid droplet-associated protein (HILPDA) and cystathionine ß-synthase (CBS) co-contribute to protecting intestinal epithelial cells from Staphylococcus aureus via regulating lipid droplets formation.

Despite Staphylococcus aureus (S. aureus) being a highly studied zoontic bacterium, its enteropathogenicity remains elusive. Herein, our findings demonstrated that S. aureus infection led to the accumulation of lipid droplets (LDs) in intestinal epithelial cells, accompanied by marked elevation inflammatory response that ultimately decreases intracellular bacterial load. The aforestated phenomenon may be partly attributed to the up-regulation of hypoxia-inducible lipid droplet-associated protein (HILPDA) and the concomitant down-regulation of cystathionine ß-synthase (CBS) protein. Moreover, S. aureus infection up-regulated the expression of HILPDA, thereby promoting LDs accumulation, and down-regulated that of CBS, consequently inhibiting microsomal triglyceride transfer protein (MTTP) expression. This process may suppress the transport of LDs to the extracellular environment, further contributing to the formation of intracellular LDs. In summary, the results of this study provide significant insights into the intricate mechanisms through which the host organism combats pathogens and maintains the balance of sulfur and lipid metabolism. These findings not only enhance our understanding of the host's defense mechanisms but also offer promising avenues for the development of novel strategies to combat intestinal infectious diseases.

Expression and prognostic significance of microsomal triglyceride transfer protein in brain tumors: a retrospective cohort study.

Background: Glioblastoma (GBM) is the most common malignant brain tumor and has poor survival. An elevated cholesterol level is involved occurrence and progression of brain tumors. Microsomal triglyceride transfer protein (MTTP) is a target for lowering lipids, and its inhibition helps to improve hyperlipidemia. However, whether the altered expression of MTTP affects the development and prognosis of brain tumors is currently unidentified. The purpose of this study is to determine MTTP as a prognostic marker for brain tumors. Methods: Data for patients with brain cancers and control brain tissue were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The datasets were analyzed using Mann-Whitney U-test or t-test to compare the expression of MTTP in normal and brain tumor tissues. To examine whether MTTP affected the prognosis of patients with brain tumors, log-rank test and multivariable Cox proportional hazard regression were conducted. Results: The expression of MTTP was significantly upregulated in brain tumors and was correlated with age, tumor stage, and isocitrate dehydrogenase (IDH) mutation. Importantly, increased MTTP expression in brain tumors is associated with poor patient survival. Conclusions: High MTTP expression is associated with brain tumor development, tumor stage, and prognosis. Therefore, MTTP is an independent prognostic indicator for brain tumors, which can serve as one of the possible targets for adjuvant treatment of GBM.

High carrier frequency for abetalipoproteinemia and evidence of a founder variant in a French-Canadian population.

Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by bi-allelic pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene. This disease is characterized by a deficiency in the secretion of apolipoprotein B-containing lipoproteins. Patients with ABL present with neurological, hematological, and gastrointestinal symptoms due to fat malabsorption and a deficiency in liposoluble vitamins. In this report, we present a total of four ABL cases, including three new cases, all originating from the same French-Canadian founder population in Saguenay-Lac-Saint-Jean, Québec, Canada. These individuals are homozygous for the same pathogenic variant in the MTTP gene (c.419dup, p.Asn140Lysfs*2). We found that this variant is more common than anticipated in this population, with an estimated carrier frequency of 1:203. Early diagnosis is essential to initiate treatment known to prevent complications associated with ABL. Population carrier screening or newborn screening for ABL should be considered in this French-Canadian founder population.

A New Case of Abetalipoproteinemia Caused by Novel Compound Heterozygote Mutations in the MTTP Gene without Fat or Vitamin Malabsorption.

Abetalipoproteinemia (ABL) is a rare disease characterized by extremely low apolipoprotein B (apoB)-containing lipoprotein levels, dietary fat, and fat-soluble vitamin malabsorption, leading to gastrointestinal, neuromuscular, and ophthalmological symptoms. We herein report a case of ABL with novel compound heterozygous mutations in the microsomal triglyceride transfer protein gene (c.1686_1687del [p.Ser563TyrfsTer10] and c.1862T>C [p.Ile621Thr]), identified via panel sequencing. Although the patient had extremely reduced low-density lipoprotein cholesterol levels and a fatty liver, he did not exhibit other typical complications. Furthermore, unlike typical ABL, this patient had a preserved apoB-48 secretion and increased concentrations of high-density lipoprotein cholesterol, which may account for the normal serum fat-soluble vitamin levels.

A new family with a case of severe early-onset muscle fatigue and a peculiar maternally inherited painful swelling in chewing muscles associated with homoplasmic m.15992A>T mutation in mitochondrial tRNAPro.

A 16-year-old boy was evaluated for a history of exercise-induced fatigability associated with nausea even after minimal effort, lower limbs muscle hypotrophy, and swelling of the masseter muscles after chewing. Laboratory tests were remarkable for hyperlactatemia and metabolic acidosis after short physical activity. The muscle biopsy showed non-specific mitochondrial alterations and an increase in intrafibral lipids. Biochemical analysis showed reduced activity of the respiratory chain complexes. Mitochondrial DNA sequencing revealed the presence of a homoplasmic variant m.15992A>T in the MT-TP gene, coding for the mt-tRNAPro in the patient, in his mother and in his brother. Pathogenic or likely pathogenic variants in MT-TP gene are rare. They are responsible for different clinical presentation, almost ever involving the muscle tissue. We report the first family with exercise-induced muscle weakness and swelling of the chewing muscles due to m.15992A>T variant in absence of J1c10 haplogroup, confirming its pathogenicity.