The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Bini, Simone; D’Erasmo, Laura; Costanzo, Alessia Di; Minicocci, Ilenia; Pecce, Valeria; Arca, Marcello

doi:10.3390/ijms22020742

Cited by 23 publications

(20 citation statements)

References 114 publications

(163 reference statements)

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“…ANGPTL3 can significantly inhibit the phospholipase activity of endothelial lipase, resulting in reduced plasma HDL-protein hydrolysis [ 17 ]. ANGPTL3 can specifically bind to adipocytes and promote the release of fatty acids and glycerol from adipocytes to the liver, where they are further converted into triglycerides and glucose, resulting in an increase in the content of free fatty acids in the plasma [ 4 , 18 ]. Recent studies have also revealed that ANGPTL3 and ANGPTL8 interact synergistically to significantly enhance the inhibition of LPL activity [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome

Zhong

Liu

et al. 2022

Lipids Health Dis

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Background It is unclear why primary nephrotic syndrome (PNS) patients often have dyslipidemia. Recent studies have shown that angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipid metabolism. In this study, we explored how ANGPTL3 impacts dyslipidemia during PNS development. Methods We measured the serum levels of ANGPTL3 in PNS patients (n=196). Furthermore, the degree of proteinuria and lipid metabolism were examined in angptl3-overexpressing transgenic (angptl3-tg) mice at different ages. Moreover, in this study, we used the clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system to create angptl3-knockout (angptl3-/-) mice to investigate lipopolysaccharide (LPS)-induced nephrosis. Results Compared with that in the healthy group, the serum level of ANGPTL3 in the PNS group was significantly increased (32 (26.35-39.66) ng/ml vs. 70.44 (63.95-76.51) ng/ml, Z =-4.81, P < 0.001). There were significant correlations between the serum level of ANGPTL3 and the levels of cholesterol (r=0.34, P < 0.001), triglycerides (r= 0.25, P = 0.001) and low-density lipoprotein (r= 0.50, P < 0.001) in PNS patients. With increasing age, angptl3-tg mice exhibited increasingly severe hypertriglyceridemia and proteinuria. The pathological features of angptl3-tg mice included rich lipid droplet deposition in hepatocytes and diffuse podocyte effacement. Compared to wild-type mice, angptl3-/- mice showed significantly lower degrees of lipid dysfunction and proteinuria after stimulation with LPS. The effects of ANGPTL3 on nephrotic dyslipidemia were confirmed in cultured hepatocytes subjected to angptl3 knockdown or overexpression. Finally, significant alterations in lipoprotein lipase (LPL) levels were observed in liver tissues from Angptl3-/- and wild-type mice stimulated with LPS. Conclusions ANGPTL3 could be involved in the development of dyslipidemia, as well as proteinuria, during PNS pathogenesis. Inhibition of LPL expression may the mechanism by which ANGPTL3 induces hyperlipidemia in PNS.

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Section: Discussionmentioning

confidence: 99%

ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome

Zhong

Liu

et al. 2022

Lipids Health Dis

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“…Statins, which inhibit the synthesis of cholesterol in the liver, lower LDL-C more than non-HDL-C and relatively more than the molar quantity of ApoB [28] , indicating that reduction of cholesterol is not sufficient to control the hepatic secretion of all the ApoB-containing lipoproteins. Elegant Mendelian randomization studies that mimic the effects of CETP inhibitors and statins, by combining variants in the cholesterol ester transfer protein (CETP, in charge of exchanging cholesterol between VLDL and high density lipoproteins) and the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR, the rate limiting step enzyme for cholesterol synthesis) genes (to create genetic scores) robustly affirmed the relevance in targeting ApoB, as a unique direct marker of both LDL and liver-derived VLDL and remnants [29] . In fact, a CETP score at or above the median was associated with lower levels of LDL-C, lower ApoB, and consistently lower CVD risk.…”

Section: Liver-derived Lipoproteins As Potent Cardiovascular Risk Pre...mentioning

confidence: 95%

“…However, the effect of both scores together was additive for LDL-C but not for ApoB or CVD risk. Indeed, the reduction of LDL-C in people harboring both scores equated to the sum of each independent score, although the extent of the reduction in ApoB and CVD risk were attenuated in people harboring both scores vs. those achieved by a single score [29] . Thus, Mendelian randomization indicates that the primary mechanism of benefit from lowering LDL-C relates to the lowering of the number of LDL particles, i.e., to the lowering of ApoB.…”

Section: Liver-derived Lipoproteins As Potent Cardiovascular Risk Pre...mentioning

confidence: 98%

Liver-derived lipoproteins and inflammation: from pathophysiology to pharmacological targets in metabolic liver disease

Baragetti¹

2022

Metab Target Organ Damage

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Low density lipoproteins (LDL) reduction remains the key goal for reducing the risk of atherosclerotic cardiovascular diseases (CVD) in people with high residual risk and metabolic complications including liver disease. Notwithstanding, epidemiological projections support a key role of liver-derived apolipoprotein B (ApoB) containing lipoproteins, namely very low density lipoproteins (VLDL) and their “remnants” (TG), undergoing the activity of lipases, in eliciting atherosclerotic inflammatory sequelae of a comparable order of magnitude to that of LDL. Disparate experimental evidence supports that triglycerides (TG), residual cholesterol content, or the large apolipoprotein set on the surface of these lipoproteins can elicit a number of plausible immune-inflammatory mechanisms that foster the vascular atherosclerotic process. Therapeutic options that convincingly lowered the plasma levels of liver-derived ApoB containing lipoproteins, either by reducing the hepatic synthesis or by improving the peripheral lipolysis of the lipid content, did not exert robust CVD risk reduction, and the effect on inflammation was questionable. Understanding the mechanisms linking liver-derived lipoproteins with chronic inflammation will provide pathophysiological insights for the identification of new therapeutic targets for people at high CVD risk and with metabolic complications. In this perspective, this topic is of immediate interest for the prevention of CVD in patients affected by non-alcoholic fatty liver disease (NAFLD) and, even more, for NAFLD patients with diabetes, insulin resistance, or other comorbidities (metabolic-associated fatty liver disease). This review resumes the principal physio-pathological insights regarding the metabolism of liver-derived lipoproteins and provides an update on the current pharmacological options that can be considered for improving CVD prevention in metabolic liver diseases.

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“…ANGPTL3 is a known inhibitor of LPL and favors the dietary triglycerides to be stored in adipose tissue during feeding [47,48]. Homozygous loss-of-function mutations in ANGPTL3 are responsible for a phenotype that is known as familial hypobetalipoproteinemia type 2 (FHBL2) (OMIM #605019).…”

Section: Evinacumabmentioning

confidence: 99%

Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

D’Erasmo

Bini

Arca

2021

Curr Atheroscler Rep

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Purpose of Review This review aims to summarize the most recent published literature concerning lomitapide and volanesorsen that are approved for the use in HoFH and FCS patients, respectively. Moreover, it will briefly revise the published evidence on novel, non-approved treatments that are under evaluation for the management of these rare forms of dyslipidemias Recent Findings The definition of rare dyslipidemias identifies a large number of severe disorders of lipid metabolism of genetic origin. Among them were homozygous familial hypercholesterolemia (HoFH) (OMIM #143890) and familial chylomicronemia syndrome (FCS) (OMIM #238600), which are characterized by a markedly impaired cholesterol- and triglyceride-containing lipoproteins metabolism. They are being particularly associated with poor health outcomes and quality of life. Considering the severity of these diseases, common lipid-lowering drugs are often ineffective or do not allow to achieve the recommended lipid targets to prevent the development of complications. Nowadays, several new drugs have been found to effectively treat HoFH and FCS with an acceptable safety profile. Summary Treating patients with HoFH and FCS remains very challenging. However, novel treatment options are emerging and might be considered in addition to conventional therapy for managing these diseases. These novel drugs will possibly change the natural history of these two rare and life-threatening diseases.

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The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Cited by 23 publications

References 114 publications

ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome

ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome

Liver-derived lipoproteins and inflammation: from pathophysiology to pharmacological targets in metabolic liver disease

Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

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