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.

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.

暂无摘要。

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare and devastating genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) leading to an increased risk of premature atherosclerosis. Patients with Homozygous familial hypercholesterolemia mostly present with mutations in LDLR; however, herein, we present two cases with concomitant microsomal triglyceride transfer protein mutations, who showed different clinical courses and treatment adherence on long-term therapy with the new MTTP inhibitor lomitapide. Objectives: We aimed to present the possibility of preventing the progression of atherosclerotic burden with effective and safe LDL-C reduction in patients with Homozygous familial hypercholesterolemia on low-dose lomitapide therapy and emphasize the role of treatment adherence in therapy success. Methods: We present two patients with phenotypically Homozygous familial hypercholesterolemia, a compound heterozygous woman and a simple homozygous man, both with LDLR and additional MTTP mutations, who were treated with the MTTP-inhibiting agent lomitapide, with different treatment compliances. The role of impulsivity was investigated through Barratt Impulsivity Scale 11, and the extent of the atherosclerotic burden was followed up using coronary artery calcium scoring, echocardiographic and sonographic findings, and, eventually, through a strict follow-up of laboratory parameters. The patients were on lomitapide for 8 and 5 years, respectively, with no adverse effects. Conclusion: When accompanied by good adherence to therapy, low-dose lomitapide on top of standard lipid-lowering therapy with decreased frequency of lipid apheresis prevented the progression of atherosclerotic burden. Non-compliance might occur due to patient impulsivity and non-adherence to a low-fat diet.

\"Normotriglyceridemic abetalipoproteinemia (ABL)\" was originally described as a clinical entity distinct from either ABL or hypobetalipoproteinemia. Subsequent studies identified mutations in APOB gene which encoded truncated apoB longer than apoB48. Therefore, \"Normotriglyceridemic ABL\" can be a subtype of homozygous familial hypobetalipoproteinemia. Here, we report an atypical female case of ABL who was initially diagnosed with \"normotriglyceridemic ABL\", because she had normal plasma apoB48 despite the virtual absence of apoB100 and low plasma TG level. Next generation sequencing revealed that she was a compound heterozygote of two novel MTTP mutations: nonsense (p.Q272X) and missense (p.G709R). We speculate that p.G709R might confer residual triglyceride transfer activity of MTTP preferentially in the intestinal epithelium to the hepatocytes, allowing production of apoB48. Together, \"normotriglyceridemic ABL\" may be a heterogenous disorder which is caused by specific mutations in either APOB or MTTP gene.

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜15 mg/dL and apoB ＜15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

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.

OBJECTIVE: Postprandial lipemia is characterized by an increase in triglyceride-rich lipoproteins after fatty meals. MicroRNAs (miRs) play important roles in lipid and lipoprotein metabolism. The aim of this study was to determine relationship between levels of plasma miR expression and lipoprotein metabolism-related proteins in subjects with normal (NPR) and high postprandial response (HPR) in postprandial period.
METHODS: The oral fat tolerance test was applied to 22 individuals with NPR and 22 with HPR.
RESULTS: Increased expressions of miR-122 and miR-33a and miR-122/30c ratio and decreased miR-30c expression were observed in fasting and postprandial period of HPR compared with NPR. ROC curve analysis showed that miR-122/30c ratio is a good biomarker for postprandial lipemia (AUC: 0.97, p < 0.001). Levels of TG, MTTP, and Apo B-48 and chylomicron (CM) particle size were significantly higher in HPR than in NPR (p < 0.05). The miR-122/30c ratio at 2 h was positively correlated with CM particle size, and with TG, MTTP and Apo B-48 levels at 4th hour. miR-33a expression decreased in HPR and was negatively correlated with ABCA1 and Apo A-1 levels at 4th hour of the postprandial period in both groups.
CONCLUSIONS: Increased miR-122 and decreased miR-30c expression levels in HPR may play critical roles in elevated or prolonged postprandial lipemia. The miR122/30c ratio exhibited good association with MTTP, Apo B-48 and TG levels, and with CM particle size, and may be a reliable marker for evaluating postprandial lipemia. miR-33a may also play a key role in decreased HDL-C in postprandial lipemia.

OBJECTIVE: : The role of two polymorphisms rs1800591 and rs3816873 of the microsomal triglyceride transfer protein (MTTP) gene in the development of nonalcoholic fatty liver disease (NAFLD) remains controversial. A meta-analysis was conducted to determine the correlation between these MTTP polymorphisms and NAFLD.
METHODS: : A systematic search was carried out using PubMed, Embase, and Cochrane Library to retrieve English studies that reported the relationship between MTTP polymorphisms (rs1800591 and rs3816873) and NAFLD published before February 18, 2020. Odds ratio (OR) and 95% confidence interval (CI) were used to appraise the risk of MTTP polymorphism in NAFLD.
RESULTS: : A total of 10 case-control studies, including 1388 cases and 1690 healthy subjects, were included. No significant correlation between the rs1800591 (G vs. T: OR = 1.08, 95% CI = 0.68-1.70, P = 0.76) and rs3816873 (CT + CC vs. TT: OR = 1.23, 95% CI = 0.76-2.01, P = 0.398) polymorphisms of MTTP and NAFLD was found in any of the models. However, when NASH patients confirmed by liver biopsy were extracted alone for rs1800591 polymorphism analysis, it was found that the G allele significantly increased the risk of NASH under the heterozygote model (GT vs. TT: OR = 3.16, 95% CI = 1.13-8.83, P = 0.028) and dominant model (GT + GG vs. TT: OR = 3.03, 95% CI = 1.13-8.09, P = 0.027).
CONCLUSIONS: The present meta-analysis revealed that the rs1800591 and rs3816873 polymorphisms of the MTTP gene are uncommon in NAFLD. However, the G allele of rs1800591 was more likely to be correlated to NASH susceptibility.

Emerging in vivo and vitro data suggest that white tea extract (WTE) is capable of favourably modulating metabolic syndrome, especially by ameliorating abnormal lipid metabolism. Microarray-based gene expression profiling was performed in HepG2 cells to analyze the effects of WTE from a systematic perspective. Gene Ontology and pathway analysis revealed that WTE significantly affected pathways related to lipid metabolism. WTE significantly downregulated apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression and thereby reduced the production of very-low-density lipoprotein. In the meanwhile, WTE stimulated low-density lipoprotein-cholesterol (LDL-c) uptake through targeting low-density lipoprotein receptor (LDLR), as a consequence of the activation of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator-activated receptor δ (PPARδ). Furthermore, WTE significantly downregulated triglycerides synthetic genes and reduced intracellular triglycerides accumulation. Besides, we demonstrated that the tea catechins epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) are abundant in WTE and contribute to the regulation of cholesterol metabolism related genes, including LDLR, MTTP and APOB. Our findings suggest white tea plays important roles in ameliorating abnormal lipid metabolism in vitro.