DEAD-Box Helicase 17 exacerbates non-alcoholic steatohepatitis via transcriptional repression of cyp2c29, inducing hepatic lipid metabolism disorder and eliciting the activation of M1 macrophages.

OBJECTIVE: Our study was to elucidate the role of RNA helicase DEAD-Box Helicase 17 (DDX17) in NAFLD and to explore its underlying mechanisms. METHODS: We created hepatocyte-specific Ddx17-deficient mice aim to investigate the impact of Ddx17 on NAFLD induced by a high-fat diet (HFD) as well as methionine and choline-deficient l-amino acid diet (MCD) in adult male mice. RNA-seq and lipidomic analyses were conducted to depict the metabolic landscape, and CUT&Tag combined with chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted. RESULTS: In this work, we observed a notable increase in DDX17 expression in the livers of patients with NASH and in murine models of NASH induced by HFD or MCD. After introducing lentiviruses into hepatocyte L02 for DDX17 knockdown or overexpression, we found that lipid accumulation induced by palmitic acid/oleic acid (PAOA) in L02 cells was noticeably weakened by DDX17 knockdown but augmented by DDX17 overexpression. Furthermore, hepatocyte-specific DDX17 knockout significantly alleviated hepatic steatosis, inflammatory response and fibrosis in mice after the administration of MCD and HFD. Mechanistically, our analysis of RNA-seq and CUT&Tag results combined with ChIP and luciferase reporter assays indicated that DDX17 transcriptionally represses Cyp2c29 gene expression by cooperating with CCCTC binding factor (CTCF) and DEAD-Box Helicase 5 (DDX5). Using absolute quantitative lipidomics analysis, we identified a hepatocyte-specific DDX17 deficiency that decreased lipid accumulation and altered lipid composition in the livers of mice after MCD administration. Based on the RNA-seq analysis, our findings suggest that DDX17 could potentially have an impact on the modulation of lipid metabolism and the activation of M1 macrophages in murine NASH models. CONCLUSION: These results imply that DDX17 is involved in NASH development by promoting lipid accumulation in hepatocytes, inducing the activation of M1 macrophages, subsequent inflammatory responses and fibrosis through the transcriptional repression of Cyp2c29 in mice. Therefore, DDX17 holds promise as a potential drug target for the treatment of NASH.

PM2.5 induced liver lipid metabolic disorders in C57BL/6J mice.

PM2.5 can cause adverse health effects via several pathways, such as inducing pulmonary and systemic inflammation, penetration into circulation, and activation of the autonomic nervous system. In particular, the impact of PM2.5 exposure on the liver, which plays an important role in metabolism and detoxification to maintain internal environment homeostasis, is getting more attention in recent years. In the present study, C57BL/6J mice were randomly assigned and treated with PM2.5 suspension and PBS solution for 8 weeks. Then, hepatic tissue was prepared and identified by metabolomics analysis and transcriptomics analysis. PM2.5 exposure can cause extensive metabolic disturbances, particularly in lipid and amino acids metabolic dysregulation.128 differential expression metabolites (DEMs) and 502 differently expressed genes (DEGs) between the PM2.5 exposure group and control group were detected. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in two disease pathways, non-alcoholic fatty liver disease (NAFLD) and type II diabetes mellitus (T2DM), and three signaling pathways, which are TGF-beta signaling, AMPK signaling, and mTOR signaling. Besides, further detection of acylcarnitine levels revealed accumulation in liver tissue, which caused restricted lipid consumption. Furthermore, lipid droplet accumulation in the liver was confirmed by Oil Red O staining, suggesting hepatic steatosis. Moreover, the aberrant expression of three key transcription factors revealed the potential regulatory effects in lipid metabolic disorders, the peroxisomal proliferative agent-activated receptors (PPARs) including PPARα and PPARγ is inhibited, and the activated sterol regulator-binding protein 1 (SREBP1) is overexpressed. Our results provide a novel molecular and genetic basis for a better understanding of the mechanisms of PM2.5 exposure-induced hepatic metabolic diseases, especially in lipid metabolism.

[Research progress on regulation of N6-adenylate methylation modification in lipid metabolism disorders].

Lipid metabolism is a complex physiological process, which is closely related to nutrient regulation, hormone balance and endocrine function. It involves the interactions of multiple factors and signal transduction pathways. Lipid metabolism disorder is one of the main mechanisms to induce a variety of diseases, such as obesity, diabetes, non-alcoholic fatty liver disease, hepatitis, hepatocellular carcinoma and their complications. At present, more and more studies have found that the "dynamic modification" of N6-adenylate methylation (m6A) on RNA represents a new "post-transcriptional" regulation mode. m6A methylation modification can occur in mRNA, tRNA, ncRNA, etc. Its abnormal modification can regulate gene expression changes and alternative splicing events. Many latest references have reported that m6A RNA modification is involved in the epigenetic regulation of lipid metabolism disorder. Based on the major diseases induced by lipid metabolism disorders, we reviewed the regulatory roles of m6A modification in the occurrence and development of those diseases. These overall findings inform further in-depth investigations of the underlying molecular mechanisms regarding the pathogenesis of lipid metabolism disorders from the perspective of epigenetics, and provide reference for health prevention, molecular diagnosis and treatment of related diseases.

Research progress on regulation of N6-adenylate methylation modification in lipid metabolism disorders / 生理学报

Lipid metabolism is a complex physiological process, which is closely related to nutrient regulation, hormone balance and endocrine function. It involves the interactions of multiple factors and signal transduction pathways. Lipid metabolism disorder is one of the main mechanisms to induce a variety of diseases, such as obesity, diabetes, non-alcoholic fatty liver disease, hepatitis, hepatocellular carcinoma and their complications. At present, more and more studies have found that the "dynamic modification" of N6-adenylate methylation (m6A) on RNA represents a new "post-transcriptional" regulation mode. m6A methylation modification can occur in mRNA, tRNA, ncRNA, etc. Its abnormal modification can regulate gene expression changes and alternative splicing events. Many latest references have reported that m6A RNA modification is involved in the epigenetic regulation of lipid metabolism disorder. Based on the major diseases induced by lipid metabolism disorders, we reviewed the regulatory roles of m6A modification in the occurrence and development of those diseases. These overall findings inform further in-depth investigations of the underlying molecular mechanisms regarding the pathogenesis of lipid metabolism disorders from the perspective of epigenetics, and provide reference for health prevention, molecular diagnosis and treatment of related diseases.

Mitochondrial dysfunction is associated with lipid metabolism disorder and upregulation of angiotensin-converting enzyme 2.

Thymidine kinase 2 (TK2) deficiency in humans leads to a myopathic form of mitochondrial DNA (mtDNA) deficiency. Here we present a skeletal and cardiac muscle specific TK2 knockout mouse (mTk2 KO). The mice showed dilated hearts and markedly reduced adipose tissue during week 12 to 16. A severe decrease of mtDNA was found only in skeletal muscle and heart tissue in mTk2 KO mice. Expression analysis of key metabolic genes of 16 weeks knockout mice showed significant changes of genes involved in lipid metabolism, with different patterns in heart and skeletal muscle. Our study further suggests that lipoprotein lipase (LPL) from liver supports the metabolism when heart and skeletal muscle were impaired due to mitochondrial dysfunction. The angiotensin-converting enzyme 2 (ACE2), which is involved in glucose homeostasis, was also affected by mtDNA deficiency in our study. Interestingly, both the gene and protein expression of ACE2 were increased in cardiac tissue of mTk2 KO mice. Since ACE2 is a receptor for the SARS-CoV-2 virus, its regulation in relation to mitochondrial function may have important clinical implications.

Comparison of two polygenic risk scores to identify non-monogenic primary hypocholesterolemias in a large cohort of Italian hypocholesterolemic subjects.

BACKGROUND: Primary Hypobetalipoproteinemias (HBL) are a group of dominant and recessive monogenic genetic disorders caused by mutations in APOB, PCSK9, ANGPTL3, MTTP, Sar1b genes and characterized by plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in a given population. Mutations in the candidate genes account only for a small proportion of subjects with HBL suggesting a role for a polygenic contribution to the low cholesterol phenotype. OBJECTIVE: To explore the complex genetic architecture of HBL we compared two polygenic risk scores in order to assess the role of the polygenic burden and the differences in the clinical phenotype between monogenic and polygenic HBL; we studied a cohort of 170 subjects with primary HBL referred over a 25-year period to 2 Italian reference centers have been studied. METHODS: The genetic analyses have been based on: Sanger sequencing, in-house NGS customized panel and two scores, PRS1 and PRS2 for the polygenic burden. RESULTS: Sixty 60 (35%) and 63 (37%) subjects had a monogenic and polygenic HBL respectively. LDL-C plasma levels were significantly lower in monogenic HBL (30.87 ± 3.12 mg/dl) compared with the non-monogenic HBL (42.80 ± 2.18 mg/dl) (p<0.002) with no differences in the percentage of fatty liver. CONCLUSION: Only PRS1 is effective in detecting polygenic HBL while PRS2 does not improve the polygenic diagnosis.

Farnesoid X Receptor Deficiency Induces Hepatic Lipid and Glucose Metabolism Disorder via Regulation of Pyruvate Dehydrogenase Kinase 4.

Farnesoid X receptors (FXR) are bile acid receptors that play roles in lipid, glucose, and energy homeostasis. Synthetic FXR-specific agonists have been developed for treating nonalcoholic fatty liver disease (NAFLD) patients. However, the detailed mechanism remains unclear. To investigate the effects of FXR on NAFLD and the possible mechanism, FXR-null mice were fed either a normal or a high-fat diet. The FXR-null mice developed hepatomegaly, steatosis, accumulation of lipid droplets in liver cells, glucose metabolism disorder, and elevated serum lipid levels. Transcriptomic results showed increased expression of key lipid synthesis and glucose metabolism-related proteins. We focused on pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme involved in the regulation of glucose and fatty acid (FA) metabolism and homeostasis. Subsequently, we confirmed an increase in PDK4 expression in FXR knockout cells. Moreover, inhibition of PDK4 expression alleviated lipid accumulation in hepatocytes caused by FXR deficiency in vivo and in vitro. Our results identify FXR as a nuclear transcription factor that regulates glucose and lipid metabolism balance through PDK4, providing further insights into the mechanism of FXR agonists in the treatment of metabolic diseases.

Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, that are highly effective in reducing plasma low-density lipoprotein (LDL) cholesterol and decreasing the risk of cardiovascular events. In recent years, a multitude of variants in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) have been suggested to influence the cholesterol-lowering response. However, the vast majority of studies have analyzed the pharmacogenetic associations in populations in Europe and the USA, whereas data in other populations, including Brazil, are mostly lacking. This narrative review provides an update of clinical studies on statin pharmacogenomics in Brazilian cohorts exploring lipid-lowering response, adverse events and pleiotropic effects. We find that variants in drug transporter genes (SLCO1B1 and ABCB1) positively impacted atorvastatin and simvastatin response, whereas variants in genes of drug metabolizing enzymes (CYP3A5) decreased response. Furthermore, multiple associations of variants in PD genes (HMGCR, LDLR and APOB) with statin response were identified. Few studies have explored statin-related adverse events, and only ABCB1 but not SLCO1B1 variants were robustly associated with increased risk in Brazil. Statin-related pleiotropic effects were shown to be influenced by variants in PD (LDLR, NR1H2) and antioxidant enzyme (NOS3, SOD2, MTHFR, SELENOP) genes. The findings of these studies indicate that statin pharmacogenomic associations are distinctly different in Brazil compared to other populations. This review also discusses the clinical implications of pharmacogenetic studies and the rising importance of investigating rare variants to explore their association with statin response.

Case Studies in Pediatric Lipid Disorders and Their Management.

CONTEXT: Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. AIM: In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. CASES: We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. CONCLUSION: Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential.

MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.

A cohort study on risk factors of high-density lipoprotein cholesterol hypolipidemia among urban Chinese adults.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) hypolipidemia, a major type of dyslipidemia, has been associated with many kinds of diseases, such as stroke, coronary heart disease, obesity and diabetes, and has displayed an increasing prevalence in China. This study explores the risk factors of HDL-C hypolipidemia and makes recommendations for controlling and preventing HDL-C hypolipidemia and the diseases caused by it. METHODS: Using a retrospective cohort study design, 26,863 urban adults without dyslipidemia, diabetes, cardiovascular and cerebrovascular diseases, hepatosis, renal insufficiency and thyroid diseases were enrolled in the study between 2010 and 2015. Data on each individual were collected at the 2010 baseline year and at a follow-up medical check. A Cox regression model was constructed to evaluate the influence of potential risk factors on the outcome event- HDL-C hypolipidemia. RESULTS: The incidence of HDL-C hypolipidemia was 5.7% (1531/26863). Sex, age, body mass index (BMI), HDL-C, triglyceride (TG) and urea nitrogen (UN) were significant risk factors of HDL-C hypolipidemia. Men were more likely to develop HDL-C hypolipidemia than women during follow-up medical checks (HR = 1.258, P = 0.014). The incidence of HDL-C hypolipidemia in the over 65 years old group was higher than that of the ≤65 age group (HR = 1.276, P = 0.009). The incidence of HDL-C hypolipidemia increased with increasing BMI (HR = 1.030, P = 0.002), TG (HR = 1.321, P = 0.001) and UN (HR = 1.054, P = 0.019), while falling with increasing HDL-C in the baseline year (HR = 0.002, P < 0.001). CONCLUSIONS: Men, aged over 65, with high BMI were at the highest risk of developing HDL-C hypolipidemia. Measures should be taken to prevent HDL-C hypolipidemia even for healthy urban adults whose blood biochemical indicators were in the normal range when their level of TG, UN and HDL-C are closed to the border of the normal value range.

The role of miR-320 in glucose and lipid metabolism disorder-associated diseases.

Glucose and lipids are important nutrients that provide the majority of energy for each organ to maintain homeostasis of the body. With the continuous improvement in living standards, the incidence of metabolic disorder-associated diseases, such as diabetes, hyperlipidemia, and atherosclerosis, is increasing worldwide. Among them, diabetes, which could be induced by both glucose and lipid metabolic disorders, is one of the five diseases with the highest incidence and mortality worldwide. However, the detailed molecular mechanisms underlying glucose and lipid metabolism disorders and target-organ damage are still not fully defined. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs, which usually affect their target mRNAs in the cytoplasm by post-transcriptional regulation. Previously, we have found that miR-320 contributed to glucose and lipid metabolism via different signaling pathways. Most importantly, we identified that nuclear miR-320 mediated diabetes-induced cardiac dysfunction by activating the transcription of fatty acid metabolic genes to cause lipotoxicity in the heart. Here, we reviewed the roles of miR-320 in glucose and lipid metabolism and target-organ damage.

A Metabolically Unhealthy Phenotype Is Associated with ADIPOQ Genetic Variants and Lower Serum Adiponectin Levels.

BACKGROUND: Even though excessive adipose tissue is related to chronic metabolic disturbances, not all subjects with excess weight (EW) display metabolic alterations, and not all normal-weight (NW) subjects have a metabolically healthy (MH) phenotype, probably due to gene-environment interactions. The aim of this study was to investigate the interaction effects of ADIPOQ and PPARG genetic variants in NW and EW individuals with different metabolic phenotypes. METHODS: Data on 345 adults from western Mexico were analyzed. The individuals were classified into NW and EW groups according to body mass index, and were categorized as MH or metabolically unhealthy (MUH), considering homeostatic model assessment insulin resistance (HOMA-IR) and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) cut-off points for glucose, triglycerides, high-density lipoprotein cholesterol, and blood pressure. Subjects with ≤1 altered parameter were classified as MH. The single nucleotide polymorphisms (SNPs) -11377C>G, -11391G>A, +45T>G, and +276G>T for ADIPOQ and Pro12Ala for PPARG were analyzed by allelic discrimination. High-molecular-weight adiponectin isoform levels were measured by ELISA. RESULTS: Lower serum adiponectin levels were associated with the MUH phenotype in EW subjects. NW subjects with the GG or TG genotype for the +45T>G SNP had reduced odds of the MUH phenotype. Individuals who carried two copies of the GG haplotype at the -11391G>A and -11377C>G SNPs for ADIPOQ had lower serum adiponectin levels than those with zero copies. CONCLUSION: In this population, lower serum adiponectin levels were found in the EW-MUH phenotype, and no differences were observed between the NW-MH and the EW-MH phenotype. In addition, the +45T>G SNP was associated with reduced odds of the MUH phenotype.

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study.

Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. This study aims to examine the causal clinical effects of blood iron and copper with Mendelian randomization (MR) analyses. Genetic instruments for the blood levels of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and a wide range of phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by MR analyses, with replication in independent data sources where possible. We found that genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.67-0.85, p = 1.90 × 10-6 for iron; OR = 0.88, 95% CI: 0.78-0.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85-0.96, p = 6.44 × 10-4; OR = 0.92, 95% CI: 0.87-0.98, p = 5.51 × 10-3) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84-0.95, p = 5.34 × 10-4; OR = 0.93, 95% CI: 0.89-0.99, p = 0.022). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the presence of pleiotropy and the robustness of causal estimates. Regardless of the approaches, consistent evidence was obtained. Moreover, the unique clinical effects of each blood mineral were identified. Notably, genetically predicated higher blood iron is associated with an enhanced risk of varicose veins (OR = 1.28, 95% CI: 1.15-1.42, p = 4.34 × 10-6), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02-1.13, p = 0.010). Sex-stratified MR analysis further revealed some degree of sex differences in their clinical effects. Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable nature of blood mineral status and the potential for clinical intervention, these findings warrant further investigation.

Lycopene Prevents DEHP-Induced Liver Lipid Metabolism Disorder by Inhibiting the HIF-1α-Induced PPARα/PPARγ/FXR/LXR System.

Di(2-ethylhexyl) phthalate (DEHP) is a widespread pollutant that badly affects animals and human health. Lycopene (LYC) has been used as a dietary supplement that has effective antioxidant and antiobesity functions. The present goal was to understand the molecular mechanisms of LYC preventing DEHP-induced lipid metabolism of the liver. The mice were intragastrically administered with LYC (5 mg/kg) and/or DEHP (500 mg/kg or 1000 mg/kg). Here, we found that LYC attenuated DEHP-caused hepatic histopathological lesions including steatosis. Hematological and biochemical analyses revealed that LYC ameliorated DEHP-caused liver function and lipid metabolism disorders. DEHP caused lipid metabolism disorders via activating the peroxisome proliferator activated receptor α/γ (PPARα/γ) signal transducer and Farnesoid X receptor (FXR)/liver X receptor (LXR) signaling pathway. As a major regulator of lipid metabolism, hypoxia-inducible factor-1α (HIF-1α) system was elevated with increased fatty degeneration under DEHP exposure. However, LYC could decrease the levels of HIF-1α/PPARα/PPARγ/FXR/LXR signaling pathway-related factors. Our research indicated that LYC could prevent DEHP-induced lipid metabolism disorders via inhibiting the HIF-1α-mediated PPARα/PPARγ/FXR/LXR system. This study may provide a possible molecular mechanism for fatty liver induced by DEHP.

Not So Slim Anymore-Evidence for the Role of SUMO in the Regulation of Lipid Metabolism.

One of the basic building blocks of all life forms are lipids-biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions and functions of lipids with the physiology of the organism. One type of control on the activity of those enzymes is the conjugation of the Small Ubiquitin-like Modifier (SUMO) that in recent years has been identified as a critical regulator of many biological processes. In this review, I summarize the current knowledge about the role of SUMO in the regulation of lipid metabolism. In particular, I discuss (i) the role of SUMO in lipid metabolism of fungi and invertebrates; (ii) the function of SUMO as a regulator of lipid metabolism in mammals with emphasis on the two most well-characterized cases of SUMO regulation of lipid homeostasis. These include the effect of SUMO on the activity of two groups of master regulators of lipid metabolism-the Sterol Regulatory Element Binding Protein (SERBP) proteins and the family of nuclear receptors-and (iii) the role of SUMO as a regulator of lipid metabolism in arteriosclerosis, nonalcoholic fatty liver, cholestasis, and other lipid-related human diseases.

IGF1 gene is epigenetically activated in preterm infants with intrauterine growth restriction.

BACKGROUND: IGF1 is a key molecule in the regulation of growth and metabolism. Low IGF1 secretion is known to cause growth restriction in childhood, as well as deregulated lipid metabolism, cardiovascular disease, and diabetes in adulthood. The IGF1 gene P2 promoter is highly methylated, resulting in low secretion of IGF1 in small infants and children. However, it is unknown when this methylation occurs. The aim of study was to clarify the point when this epigenetic program occurs during intrauterine development. We analyzed 56 preterm infants born before 32 weeks of gestation, including 19 intrauterine growth restriction (IUGR) infants whose birth weights were lower than - 2SD calculated by the Japanese datasets. We extracted genomic DNA from whole blood at birth; methylation of the six CpG sites in the IGF1 P2 promoter was analyzed by the bisulfite amplicon method using the MiSeq platform. RESULTS: In contrast to term infants and children, the methylation of all six CpG sites positively correlated with body weight and body length at birth. IGF1 P2 promoter methylation levels were significantly reduced in all six CpG sites in infants with IUGR. CONCLUSIONS: These findings indicated that the IGF1 gene is epigenetically activated before 32 weeks of gestation in infants with IUGR and that the activated gene may become suppressed after this time point. This study may provide new insights to prevent the onset of adult diseases and to aid in nutritional management for preterm birth infants in neonatal intensive care units.

Genetic characteristics and follow-up of patients with fatty acid ß-oxidation disorders through expanded newborn screening in a Northern Chinese population.

Background Fatty acid ß-oxidation disorders (FAODs) include more than 15 distinct disorders and have a wide variety of symptoms, usually not evident between episodes of acute decompensation. After the introduction of newborn screening (NBS) using tandem mass spectrometry (MS/MS), early identification of FAODs has become feasible. We analyzed the MS/MS results in Tianjin, China during a six-year period to evaluate the incidence, disease spectrum, and genetic characteristics of FAODs. Methods We analyzed the MS/MS results for screening FAODs from May 2013 to December 2018 in Tianjin, China. Infants with positive screening results were confirmed through next-generation sequencing and validated by Sanger sequencing. Results A total of 220,443 infants were screened and 25 FAODs patients were identified (1:8,817). Primary carnitine deficiency (PCD) with an incidence rate up to 1:20,040 was the most common disorder among all FAODs. Recurrent mutations of relatively common diseases, like PCD and short-chain acyl-CoA dehydrogenase deficiency (SCADD), were identified. During the follow-up, two patients suffered from sudden death due to carnitine palmitoyl transferase-Ⅱ deficiency (CPT Ⅱ) and very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD). Conclusion Our data indicated that FAODs are relatively common in Tianjin and may even cause infant death in certain cases. The elucidated disease spectrum and genetic backgrounds elucidated in this study may contribute to the treatment and prenatal genetic counseling of FAODs.

Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency.

PURPOSE OF REVIEW: Angiopoietin-like protein-3 (ANGPTL3) is emerging as a key player in lipoprotein transport with an expanding role on fatty acid and glucose metabolism. Its deficiency is associated with a favorable metabolic profile. The present review will highlight the recent understanding of metabolic and cardiovascular consequences of ANGPTL3 inactivation by considering both genetic and pharmacological investigations. RECENT FINDINGS: Experimental studies have further illustrated the complex interplay between ANGPTL3 and ANGPTL4-8 in orchestrating lipid transport in different nutritional status. Individuals with familial combined hypolipidemia due to homozygous loss-of-function mutations in ANGPTL3 gene showed improved metabolism of triglyceride-rich lipoproteins during fasting and postprandial state and increased fatty acid oxidation and insulin sensitivity. Moreover, mendelian randomizations studies demonstrated that partial ANGPTL3 deficiency associates with reduced risk of atherosclerotic cardiovascular events and, eventually, diabetes mellitus. Finally, inactivation of ANGPTL3, using either a specific mAb or antisense oligonucleotide, was reported to reduce plasma levels of atherogenic lipoprotein in humans and improve hepatic fat infiltration in animal models. SUMMARY: Human and animal studies have further dissected the complex role of ANGPTL3 in the regulation of energy substrate metabolism. Moreover, genetic and pharmacological investigations have convincingly indicated that the inactivation of ANGPTL3 may be a very promising strategy to treat atherogenic metabolic disorders.

Mitochondrial and Metabolic Myopathies.

PURPOSE OF REVIEW: This article provides an overview of mitochondrial and metabolic biology, the genetic mechanisms causing mitochondrial diseases, the clinical features of mitochondrial diseases, lipid myopathies, and glycogen storage diseases, all with a focus on those syndromes and diseases associated with myopathy. Over the past decade, advances in genetic testing have revolutionized patient evaluation. The main goal of this review is to give the clinician the basic understanding to recognize patients at risk of these diseases using the standard history and physical examination. RECENT FINDINGS: Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function. In most circumstances, more than one organ system is involved in mitochondrial disease, and the value of the classic clinical features as originally described early in the history of mitochondrial diseases has reemerged as being important to identifying patients who may have a primary mitochondrial disease. The use of the genetic laboratory has become the most powerful tool for confirming a diagnosis, and nuances of using genetic results will be discussed in this article. Treatment for mitochondrial disease is symptomatic, with less emphasis on vitamin and supplement therapy than in the past. Clinical trials using pharmacologic agents are in progress, with the field attempting to define proper goals of treatment. Several standard accepted therapies exist for many of the metabolic myopathies. SUMMARY: Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature. Early recognition requires basic knowledge of the varied clinical phenotypes before moving forward with a screening evaluation and possibly a genetic evaluation. Aside from a few specific diseases for which there are recommended interventions, treatment for the majority of these disorders remains symptomatic, with clinical trials currently in progress that will hopefully result in standard treatments.