The pathophysiology of intestinal lipoprotein production

Intestinal lipoprotein production is a multistep process, essential for the absorption of dietary fats and fat-soluble vitamins. Chylomicron assembly begins in the endoplasmic reticulum with the formation of primordial, phospholipids-rich particles that are then transported to the Golgi for secretion. Several classes of transporters play a role in the selective uptake and/or export of lipids through the villus enterocytes. Once secreted in the lymph stream, triglyceride-rich lipoproteins (TRLs) are metabolized by Lipoprotein lipase (LPL), which catalyzes the hydrolysis of triacylglycerols of very low density lipoproteins (VLDLs) and chylomicrons, thereby delivering free fatty acids to various tissues. Genetic mutations in the genes codifying for these proteins are responsible of different inherited disorders affecting chylomicron metabolism. This review focuses on the molecular pathways that modulate the uptake and the transport of lipoproteins of intestinal origin and it will highlight recent findings on TRLs assembly

Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases

Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options

Heterogenous forms of dyslipidemiain women with polycystic ovary syndrome

Forms of dyslipidemia are very common in individuals affected by polycystic ovary syndrome (PCOS), but in addition to plasmatic lipids, it is necessary to evaluate the alterations in the atherogenic lipoproteins (Lp) and apolipoproteins (apo). In our study we measured the concentrations of apoB, Lp(a) and low density lipoproteins (LDL) in 42 patients with PCOS (age: 28 +/- 7 years, body mass index: 27 +/- 5 kg/m-) and 37 healthy women (of the same age and body mass index). Methods: values of Lp(a) >30 mg/dl were considered high, whereas for apoB, values >100 g/l were considered high. Results: the patients with PCOS showed an increase in triglycerides (p=0.0011) and low levels of high density lipoproteins (HDL) (p=0.0131), but the total cholesterol and the LDLs were not significantly different to those of the control group. High levels of Lp(a) were found in 24% of the individuals with PCOS, and a smaller number showed high levels of apoB (14%). This analysis shows that the concentrations of Lp(a) are only correlated to the HDL levels (r =0.378, p= 0.0431). 36% of the patients with PCOS with normal levels of plasmatic lipids show high levels of Lp(a) and apoB, and small and dense LDLs. Conclusions: alterations in the plasmatic lipids are present in 1/3 of the women affected by PCOS. More research is necessary to better understand the mechanisms responsible to reduce the risk of cardiovascular problems in young women with polycystic ovary syndrome

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details

Valutazione in vivo dello stress ossidativo e dell'attivazione piastrinica nell'ipobetalipoproteinemia familiare: confronto con l'ipercolesterolemia familiare e l'iperalfalipoproteinemia familiare

Background Oxidative stress is associated with an increased risk of atherothrombosis and platelet activation as several animal models have been shown. The increased production of reactive oxygen species (ROS) leads to lipids peroxidation of the cell membranes and of lipoproteins, high production of F2-isoprostanes from arachidonic acid, thus modulating the platelet activation induced by thromboxane. 8-iso-PGF2a and 11-deidro-tromboxane (TX)B2 are in vivo markers of oxidative stress and platelet activation, respectively. Recently it has been shown that subjects with low plasma levels of HDL (increased cardiovascular risk) present with high urinary levels of these markers. This excretion is reduced by changing life style and by pharmacological increase of HDL cholesterol. Aim and Methods The aim of this study was to evaluate in a group of FHBL subjects (n=10) the urinary levels of 8-iso-PGF2 and 11-deidro-TX B2 and to compare these finding with ADH (n=10) and HALP subjects (n=10). We have performed also the analysis of plasma markers of inflammation (IL-6), platelet (NOX-2) and endothelial activation (ICAM-1, VCAM-1) to understand the real CV risk in FHBL subjects compared to ADH and HALP patients. Results The analysis of oxidative stress, platelet and endothelial activation markers didn’t show any significant difference between FHBL and HALP subjects. Non-treated ADH exhibit higher urinary secretion of F2-isoprostanes and plasma levels of NOX-2, ICAM-1, VCAM-1 and IL-6 than FHBL and HALP subjects. After lipid lowering treatment, ADH subjects exhibit a significant decrease of all these markers. Conclusions These data confirm a linear correlation between the excretion of rates of F2-isoprostanes and subjects at high CV risk (such ADH subjects). Several limitations include small sample size of our study population. These findings may have important clinical implications for primary and secondary prevention in ADH and HALP subjects underlying possible benefits of low cholesterol plasmatic levels in FHBL subjects

Therapeutic options for homozygous familial hypercholesterolemia: the role of Lomitapide

Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the microsomal triglyceride transfer protein (MTP) approved as a novel drug for the management of homozygous familial hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine

APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism

Purpose of review: Apolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role. Recent findings: The role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimer's disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention

FISIOPATOLOGIA DELLA SINTESI DELLE LIPOPROTEINE INTESTINALI

La sintesi di lipoproteine di origine intestinale è un processo sequenziale, necessario per l’assorbimento dei lipidi e delle vitamine liposolubili di origine alimentare. L’assemblaggio dei chilomicroni inizia nel reticolo endoplasmico con la formazione di particelle ricche di fosfolipidi che sono poi trasportate al Golgi per essere secrete. Diverse classi di trasportatori giocano un ruolo sia nell’assorbimento selettivo che nel trasporto di lipidi attraverso i villi intestinali. Una volta secrete nel circolo linfatico, le lipoproteine ricche di trigliceridi (LRT) sono sottoposte all’azione della Lipasi Lipoproteica (LPL), che catalizza l’idrolisi dei triacilgliceroli delle lipoproteine a densità molto bassa (VLDL) e dei chilomicroni, recapitando in questo modo gli acidi grassi liberi ai diversi tessuti. Mutazioni a carico dei geni che codicano per queste proteine sono responsabili di disordini ereditari che coinvolgono il metabolismo dei chilomicroni. In questo articolo focalizzeremo la nostra attenzione sui meccanismi molecolari che modulano l’assorbimento e il trasporto delle lipoproteine di origine intestinale e illustreremo alcune recenti evidenze sull’assemblaggio delle LRT.Intestinal lipoprotein production is a multistep process, essential for the absorption of dietary fats and fat-soluble vitamins. Chylomicron assembly begins in the endoplasmic reticulum with the formation of primordial, phospholipids-rich particles that are then transported to the Golgi for secretion. Several classes of transporters play a role in the selective uptake and/or export of lipids through the villus enterocytes. Once secreted in the lymph stream, triglyceride-rich lipoproteins (TRLs) are metabolized by Lipoprotein lipase (LPL), which catalyzes the hydrolysis of triacylglycerols of very low density lipoproteins (VLDLs) and chylomicrons, thereby delivering free fatty acids to various tissues. Genetic mutations in the genes codifying for these proteins are responsible of different inherited disorders affecting chylomicron metabolism. This review focuses on the molecular pathways that modulate the uptake and the transport of lipoproteins of intestinal origin and it will highlight recent findings on TRLs assembl

The Burden of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: Screening Issue and Future Perspectives

In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers for the development of the disease, but also two independent risk factors for HCC. Single nucleotide polymorphisms (such as PNPLA3, TM6SF2 and MBOAT7) are related to the susceptibility to the development of HCC and its progression. Therefore, an appropriate follow-up of these patients is needed for the early diagnosis and treatment of HCC. To date, international guidelines recommend the use of ultrasonography with or without alpha-fetoprotein (AFP) in patients with advanced fibrosis. Furthermore, the use of non-invasive tools could represent a strategy to implement surveillance performance. In this review, we analyzed the main risk factors of NAFLD-related HCC, the validated screening methods and the future perspectives