Lipids in Health and Disease

Hepatitis B virus (HBV) infection correlated with the development of cirrhosis, liver failure and hepatocellular carcinoma (HCC), poses a huge health burden on the global community. However, the pathogenesis of chronic hepatitis B (CHB) remains unclear. Apolipoprotein A1 (ApoA1) mainly secreted by hepatocytes, represents the major protein component of high-density lipoprotein. ApoA1 secretion may be disrupted by HBV infection. In this study, we mainly investigated the molecular mechanism of ApoA1 down regulated by HBV for revealing the pathogenesis of CHB. ApoA1 expression in livers of CHB patients as well as healthy controls were performed by Real-time PCR (RT-PCR) and Western blot. The serum ApoA1 levels were measured by Enzymed-linked immunosorbent assay (ELISA). Expression of ApoA1 mRNA and protein levels were performed by RT-PCR and Western blot in human hepatoma HepG2 cells and subline HepG2.2.15 cells. HBV expression construct, pHBV1.3 were transfected into HepG2, the changes of ApoA1 mRNA and protein expression were detected by RT-PCR and Western blot. To further study the mechanism of ApoA1 down regulation by HBV, 11 CpG islands in ApoA1 promotor were tested for DNA methylation status by MSP. HepG2.2.15 cell lines were treated with DNA methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC), then, expression of ApoA1 mRNA and HBV particles in the supernatant, as well as ApoA1 protein levels were detected by RT-PCR and Western blot. Secretion of HBsAg and HBeAg in HepG2 cells cotransfected with pApoA1 and pHBV1.3 constructs was tested by ELISA. Meanwhile, secretion of HBsAg and HBeAg in the supernatant were quantified by ELISA in the HepG2.2.15 cells treated with 5-aza-dC plus ApoA1 siRNA. Expression of ApoA1 mRNA and protein levels, as well as serum ApoA1 levels in CHB patients were decreased corresponding healthy controls in vivo. In addition, the expression of ApoA1 mRNA and protein levels were down regulated in HepG2.2.15 cells correponding HepG2 cells, 11 CpG islands in ApoA1 promoter were tested for methylation status by MSP in HepG2.2.15 cells compared to HepG2 cells, while two CpG islands were found hypermethylated. Expression of ApoA1 mRNA and protein levels were increased in HepG2.2.15 cells treated with DNA methyltransferase inhibitor 5-aza-dC. Furthermore, overexpression of ApoA1 can enhance HBV expression in HepG2 cells while the inhibitory effect of 5-aza-dC on HBV expression was completely abolished by blocking 5-aza-dC-induced up-regulation of ApoA1 using RNAi. Epigenetic silencing of ApoA1 gene expression by CpG island DNA hypermethylation induced by HBV may contribute to the pathogenesis of CHB.

The purpose of the study was to evaluate the effects of krill oil (KO) on cognition and depression-like behaviour in rats. Cognition was assessed using the Aversive Light Stimulus Avoidance Test (ALSAT). The Unavoidable Aversive Light Stimulus (UALST) and the Forced Swimming Test (FST) were used to evaluate the antidepressant-like effects of KO. Imipramine (IMIP) was used as the antidepressant reference substance. After 7 weeks of KO intake, both males and females treated with KO were significantly better in discriminating between the active and the inactive levers in the ALSAT from day 1 of training (p<0.01). Both KO and IMIP prevented resignation/depression on the third day in the UALST. Similarly, a shorter immobility time was observed for the KO and IMIP groups compared to the control in the FST (p<0.001). These data support a robust antidepressant-like potential and beneficial cognitive effect of KO. Changes in expression of synaptic plasticity-related genes in the prefrontal cortex and hippocampus were also investigated. mRNA for brain-derived neurotrophic factor (Bdnf) was specifically upregulated in the hippocampus of female rats receiving 7 weeks of KO supplementation (p=0.04) and a similar trend was observed in males (p=0.08). Males also exhibited an increase in prefrontal cortex expression of Arc mRNA, a key protein in long-term synaptic plasticity (p=0.05). IMIP induced clear effects on several plasticity related genes including Bdnf and Arc. These results indicate that active components (eicosapentaenoic acid, docosahexaenoic acid and astaxanthin) in KO facilitate learning processes and provide antidepressant-like effects. Our findings also suggest that KO might work through different physiological mechanisms than IMIP.

Lysophosphatidic acid (LPA) is a bioactive lipid with a wide biological activity. Previous studies have shown its potential usefulness as a diagnostic marker for ovarian cancer. The aim of the study was to investigate which factors may influence plasma LPA concentrations in healthy subjects and to propose reference values. The study group consisted of 100 healthy subjects. From all of them the blood samples were taken at 7 a.m. (fasting state). From 40 volunteers additional blood samples were taken at 2 p.m., at 8 p.m. and at 2 a.m. next morning. Concentrations of LPA were measured in plasma samples using enzyme-linked immunosorbent assay. Analysis of samples from 100 healthy volunteers showed significant influence of sex and age on plasma LPA. The reference range for the plasma LPA concentration corrected for age and sex, determined at 2.5–97.5 percentile interval is 0.14–1.64 μM. LPA correlates positively with BMI, serum total cholesterol, triacylglycerols, uric acid and negatively with estimated glomerular filtration rate and serum albumin. Concentration of LPA at 2 a.m. was lower than at 2 p.m. There were not any significant differences between plasma LPA at 7 a.m. and any other time of the day. Plasma LPA is associated with demographic, anthropometric and biochemical parameters. It seems that LPA concentrations have no specific circadian rhythm and the time of donation and fasting state have marginal effect on plasma LPA. These findings may be helpful in future incorporation of LPA as a diagnostic marker.

Sleep is an integral part of good health. Sleep disorders and variations in sleep habits are associated with a low-grade inflammatory status, which may be either a cause or consequence of other conditions, including obesity, diabetes and cardiovascular disease. Several strategies are available to counteract these conditions including continuous positive airway pressure (CPAP), pharmacological and nutritional interventions, and even surgery. At present, our group is investigating the effect of chronic endurance exercise on sleep alterations.

Diabetes is often accompanied by dyslipidemia. Lipid control is very important in the management of diabetes. There are limited real world data on the lipid control in diabetic inpatients in southwest China. An observational study was conducted to assess the characteristics of lipid profiles and lipid control. Diabetic patients from February 2009 to December 2013 at West China Hospital of Sichuan University were identified. A total of 56,784 inpatients were included and 85.9% of them had at least one lipid panel. The proportions of inpatients with optimal low-density lipoprotein cholesterol (LDL-C) level (< 2.59 mmol/L), optimal triglyceride (TG) level (< 1.70 mmol/L), optimal high-density lipoprotein cholesterol (HDL-C) level (men ≥1.04 mmol/L; women ≥1.30 mmol/L) and optimal non-high-density lipoprotein cholesterol (non-HDL-C) level (< 3.37 mmol/L) were 61.1, 64.6, 49.9 and 64.5%, respectively. Only 23.1% of inpatients obtained optimal levels for all the above four lipid parameters. Of diabetic inpatients with ischemic heart disease, the proportions of inpatients with optimal LDL-C level (< 1.81 mmol/L), optimal TG level (< 1.70 mmol/L), optimal HDL-C level (men ≥1.04 mmol/L; women ≥1.30 mmol/L) and optimal non-HDL-C level (< 2.59 mmol/L) were 38.0, 66.3, 48.1 and 48.7%, respectively. Of diabetic inpatients with cerebrovascular disease, the proportions were 28.3, 64.8, 49.9 and 38.1%, respectively. Older people and men were more likely to obtain optimal lipid levels. However, inpatients between 46 and 64 years were least likely to obtain optimal LDL-C levels. The lipid control of diabetic inpatients in southwest China is worrisome. Individualized strategies of lipid management should be taken to bridge the gap between the recommendations of clinical guidelines and the real situation of clinical practice.

Proprotein convertase subtilisin/kexin type 9 (Pcsk9) correlated with incidence and prognosis of coronary heart disease. However, it is unclear whether Pcsk9 contributed to coronary artery lesion severity in patients with premature myocardial infarction (PMI). The present study investigated associations between Pcsk9 and coronary artery lesion severity in PMI patients who underwent coronary angiography (CAG). This prospective cohort study included young men (age ≤ 45 years, n = 332) with acute MI who underwent CAG between January 2017 and July 2019. Serum Pcsk9 levels and clinical characteristics were evaluated. SYNTAX scores (SYNergy between percutaneous coronary intervention with [paclitaxel-eluting] TAXUS stent and cardiac surgery) were calculated to quantify coronary artery lesions. Serum Pcsk9 levels were positively associated with SYNTAX scores (r = 0.173, P < 0.05). The diagnostic cutoff value of PSCK9 level was 122.9 ng/mL, yielding an area under the curve (AUC) of 0.63, sensitivity 81%, and specificity 40%. Serum Pcsk9, LDL-C, Apob, NT-proBnp, CK level, and diabetes history were independent predictors of high SYNTAX scores (P < 0.05). After stratifying by serum LDL-C level (cutoff = 2.6 mmol/L), medium-high Pcsk9 levels had increased risk of high SYNTAX scores in patients with high LDL-C (P < 0.05), and higher serum Pcsk9 levels had increased risk of major adverse cardiac events (MACE) after adjusting for confounding factors (P < 0.05). Serum Pcsk9 levels correlates with severity of coronary artery lesion in PMI patients and may serve as a biomarker for severity of coronary artery stenosis in this patient population, which may contribute to risk stratification.

Previous studies indicated that hyperlipidemia was associated with retinitis pigmentosa (RP). We aimed to identify the mutations in the C5L2 gene which was reported to be associated with hyperlipidemia in a Chinese family with (RP). The Proband from the family was screened for mutations in the C5L2 gene that was known to cause hyperlipidemia. Cosegregation analysis was performed in the available family members. Linkage analysis was performed for one missense mutation to calculate the likelihood of its pathogenicity. One hundred and fifty unrelated, healthy Chinese subjects were screened to exclude nonpathogenic polymorphisms. By direct sequencing method, we identified a novel mutation (Thr196Asn) in C5L2 gene. In this family, each affected family members with RP showed a heterozygous mutation in the C5L2 gene. And all the carriers with heterozygous mutation have increased serum lipid levels in this family. The present study has extended the mutation spectrum of C5L2, and Thr196Asn mutations in C5L2 were associated with RP and serum lipid levels.

Elevated stearoyl-CoA desaturase activity has been described in obese states, with an increased desaturation index (DI) suggesting enhanced lipogenesis. Differences in the DI among various phenotypes of abnormal adiposity have not been studied. Abnormal accumulation of subcutaneous adipose tissue occurs in rare adipose disorders (RADs) including Dercum's disease (DD), multiple symmetric lipomatosis (MSL), and familial multiple lipomatosis (FML). Examining the DI in subcutaneous fat of people with DD, MSL and FML may provide information on adipose tissue fatty acid metabolism in these disorders. The aims of this pilot study were: 1) to determine if differences in adipose tissue DIs are present among RADs, and 2) to determine if the DIs correlate to clinical or biochemical parameters. Subcutaneous adipose tissue was obtained from human participants with DD (n = 6), MSL (n = 5), FML (n = 8) and obese Controls (n = 6). Fatty acid composition was determined by gas chromatography/mass spectrometry. The DIs (palmitoleic/palmitic, oleic/stearic, vaccenic/stearic ratios) were calculated from the gas chromatogram peak intensities. SCD1 gene expression was determined. Spearman's correlations between the DIs and available clinical or biochemical data were performed. In DD subjects, the vaccenic/stearic index was lower (p < 0.05) in comparison to Controls. Percent of total of the saturated fatty acid myristic acid was higher in DD compared with Controls and FML. Percent of monounsaturated vaccenic acid in DD trended lower when compared with Controls, and was decreased in comparison to FML. In MSL, total percent of the polyunsaturated fatty acids was significantly lower than in the Control group (p < 0.05). In the total cohort of subjects, the palmitoleic/palmitic and oleic/stearic DIs positively correlated with age, BMI, and percent body fat. The positive associations between the DIs and measures of adiposity (BMI and percent body fat) support increased desaturase activity in obesity. The lower vaccenic/stearic DI in DD SAT compared with Controls suggests presence of other factors involved in fat accumulation in addition to lifestyle. Other mechanisms driving fat accumulation in DD such as inflammation or lymphatic dysfunction should be investigated.