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Track 2 - Metabolism of Lipids and Lipoproteins
Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Room
Hall 5
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Session Ticket
Pre-Recorded
Session Evaluation
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The role of FXR in reverse cholesterol transport

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:00 - 10:10

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G-protein coupled bile acid receptors

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:10 - 10:20

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The role of the Cyp7b1-derived cholesterol metabolites in NASH development

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:20 - 10:30

Abstract

Background and Aims

Aim:

Brown adipose tissue (BAT) activation by cold exposure induces hepatic Cyp7b1 expression, promoting cholesterol conversion to bile acids (BA) and intermediate oxysterols, mainly through the alternative synthesis pathway. Increased BAT activity inversely correlates with NAFLD progression and since BA exert anti-inflammatory properties, we aim to investigate the role of Cyp7b1 derived-metabolites during NAFLD to NASH progression.

Methods

Methods:

Cyp7b1-/- and wild type (WT) mice fed a choline-deficient high-fat diet for 8 months (diet-induced NASH model) were housed either at 30°C (thermoneutral conditions, control) or at 22°C (mild-cold exposure) to stimulate BAT and the hepatic Cyp7b1 overexpression. Metabolic parameters, histology, gene expression and protein levels were analyzed. BA/oxysterol species were determined by LC-MS/MS-based methods.

Results

Results:

Prolonged mild-cold exposure induced Cyp7b1 expression in WT mice and attenuated NASH development compared to 30oC in both genotypes (decreased plasma lipids, ALT activity, hepatic inflammation / fibrosis). Conversely, Cyp7b1-/- mice housed at thermoneutrality have an aggravated NASH phenotype compared to controls (elevated ALT activity, hepatic fibrosis, inflammatory / fibrotic gene markers, hyperlipidemia and hyperinsulinemia). Interestingly, mild cold exposure increased hepatic Cyp27a1, Ldlr and Lrp1 expression of Cyp7b1-/- mice, accompanied by ameliorated disease phenotype.

Conclusions

Conclusion:

Deletion of Cyp7b1 augments the disease’s phenotype at 30oC, suggesting that the downstream metabolites exert beneficial features during NASH manifestation at thermoneutral conditions. Upon mild cold exposure and BAT activation, the compensatory hepatic upregulation of Cyp27a1 in the Cyp7b1-/- mice together with this of Ldlr and Lrp1 indicate an enhanced lipoprotein metabolism and could, in part, explain the improved disease state.

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Δ24-Dehydrocholesterol reductase (DHCR24): a novel target for the treatment of NASH

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:30 - 10:40

Abstract

Background and Aims

24-Dehydrocholesterol reductase (DHCR24) is the terminal enzyme in cholesterol biosynthesis converting the ultimate intermediate desmosterol into cholesterol. Desmosterol is an endogenous liver X receptor ligand with anti-inflammatory properties and reduces cholesterol and fatty acid biosynthesis. We aimed to investigate the therapeutic effects of DHCR24 inhibition by using the novel selective DHCR24 inhibitor SH42 on hepatic steatosis and inflammation, the two most important hallmarks of nonalcoholic steatohepatitis (NASH).

Methods

Male APOE*3-Leiden.CETP mice, a well-established translational model for lipoprotein metabolism that develops diet-induced human-like NASH characteristics, were fed a high fat and high cholesterol diet with or without simultaneous SH42 treatment (3x0.5mg/week, i.p.). After 8 weeks, liver steatosis and inflammation were assessed. Lipidomics and lipid mediator analyses were carried out on plasma and liver.

Results

DHCR24 inhibition via SH42 markedly increased plasma desmosterol levels (+5,600%), without influencing food intake and body weight. SH42 decreased plasma cholesteryl ester (-24%) and fatty acids (-19%) levels whilst not affecting diacylglycerol(DAG) and triacylglycerol(TAG) levels. Notably, SH42 largely increased plasma 19,20-epoxydocosapentaenoic acid levels (+210%), a well described and potent anti-inflammatory/pro-resolving lipid mediator. In the liver, SH42 reduced DAG (-21%), TAG (-38%) and cholesteryl esters (-26%). Strikingly, liver histological assessment showed that SH42 abolished diet-induced hepatic steatosis, inflammation, ballooning and crown-like structure formation.

Conclusions

Inhibition of DHCR24 by SH42 abolishes hepatic steatosis, inflammation and damage as induced by a diet containing high fat and high cholesterol. DHCR24 inhibition is a potential novel therapeutic strategy for the treatment of NASH by killing two birds with one stone, i.e. hepatic steatosis and inflammation.

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Sphingosine 1-phosphate (S1P) receptor type 1 signaling induces an anti-atherogenic phenotype in macrophages and attenuates atherosclerosis in LDL-receptor-deficient mice

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:40 - 10:50

Abstract

Background and Aims

Sphingosine 1-phosphate (S1P) accounts for antiatherogenic properties of high-density lipoproteins, but the S1P receptor subtype mediating the atheroprotective effects of S1P and the underlying molecular mechanisms remain enigmatic. Experimental models engineered to amplify the signaling of endogenous S1P over its specific receptors may help in clarifying this issue. To this purpose, we generated a mouse model overexpressing S1P receptor type 1 (S1P1) specifically in the myeloid compartment and studied the effect on atherosclerosis development.

Methods

Mice overexpressing S1P1 in myeloid cells (monocytes and macrophages) were generated by crossing mice expressing the murine S1P1 gene under a promoter containing a floxed blocking element with mice expressing Cre recombinase under the control of lysozyme (LysMCre) promoter. Bone marrows from these or control mice were transplanted into low density lipoprotein receptor (LDL-R)-deficient mice and resulting chimeras were fed a Western diet for 14 weeks.

Results

S1P1 overexpressing macrophages showed increased expression and activity of transcription factors PU.1, IRF8 and LXR. This skewed macrophages towards an anti-inflammatory M2 phenotype with enhanced production of IL-10, IL-1RA and IL-5. In addition, S1P1 overexpressing macrophages showed increased ABCA1- and ABCG1-dependent cholesterol efflux, accelerated reversed cholesterol transport, enhanced expression of MerTK and Axl1 and efferocytosis, and reduced endoplasmic stress-induced apoptosis. Atherosclerotic lesion formation in aortic roots and brachiocephalic arteries as well as necrotic core formation were significantly reduced in mice overexpressing S1P1 in myeloid cells.

Conclusions

S1P1 signaling produces a unique anti-inflammatory and anti-atherogenic macrophage phenotype and countervails the development of atherosclerotic lesions in mice.

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Effects of bempedoic acid on diet-induced hepatic steatosis in female rats

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
10:50 - 11:00

Abstract

Background and Aims

Bempedoic acid (BemA), an ATP-citrate lyase (ACLY) inhibitor, reduces cholesterol and fatty acid synthesis. We explored BemA effects in the early stage of non-alcoholic fatty liver disease in a diet-induced rat model of hepatic steatosis.

Methods

Eight-week-old female Sprague-Dawley rats were randomly distributed into 3 groups (n=8): control (CT; standard rodent chow), fructose plus high fat diet (FHFD; high fat diet and 10% w/v fructose in drinking water), and FHFD plus BemA at 30 mg/Kg/day (BemA). All rats were fed the diets for three months, and BemA group was treated orally with BemA for the last month. Biochemical and zoometric parameters were determined. Beta-oxidation activity and gene/protein expression were determined in hepatic tissue.

Results

FHFD rats consumed almost twice more calories than controls, but their body weight at the end of treatment was not increased. Significant hepatic triglyceride accumulation and hypertriglyceridemia were observed in FHFD rats. Treatment with BemA reduced hepatic triglyceride accumulation and increased liver weight in comparison to FHFD. Histological images showed an increase of hepatocyte size in Bem A group in comparison to the other groups. Beta-oxidation activity was reduced in FHFD group, and treatment with BemA not only blunted this effect, but also caused a significant increase of this enzyme activity in relation to FHFD. Accordingly, BemA markedly induced the hepatic gene expression of acyl-CoA oxidase (ACO), without changes in carnitine palmitoyl transferase 1 (CPT1).

Conclusions

BemA may induce hepatic peroxisomal proliferation and reduce hepatic steatosis at least in part through increased fatty acid catabolism.

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Efficacy and Safety of Bempedoic Acid in Patients with Heterozygous Familial Hypercholesterolemia: Analysis of Pooled Patient-level Data from Phase 3 Clinical Trials

Session Type
Track 2 - Metabolism of Lipids and Lipoproteins
Date
06.10.2020, Tuesday
Session Time
10:00 - 11:13
Lecture Time
11:00 - 11:10

Abstract

Background and Aims

Patients with heterozygous familial hypercholesterolemia (HeFH) have high cardiovascular risk due to lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C), often requiring multidrug therapy to achieve sufficient LDL-C lowering. In patients with and without HeFH, we evaluated efficacy and safety of bempedoic acid (BA), an investigational, oral, once-daily, ATP-citrate lyase inhibitor, when added to existing lipid-lowering therapy (LLT).

Methods

Data were pooled from two phase 3 clinical trials that randomized (2:1) 3009 patients with atherosclerotic cardiovascular disease and/or HeFH receiving background maximally-tolerated statin therapy with or without other nonstatin LLTs to treatment with BA 180 mg or placebo once daily for 52 weeks. The primary efficacy endpoint was percent change from baseline to week 12 in LDL-C. Safety assessments included treatment-emergent adverse events (TEAEs).

Results

HeFH patients (n=112) had higher baseline LDL-C (mean [SD], BA: 3.7 [0.1] mmol/L; placebo: 4.0 [0.3] mmol/L) vs those without HeFH (n=2897) (BA: 2.7 [0.02] mmol/L; placebo: 2.7 [0.02] mmol/L). Mean LDL-C reductions from baseline to week 12 were significantly greater with BA vs placebo (P < .001) for patients with and without HeFH (placebo-corrected, HeFH: –22.3%; without HeFH: –18.3%). BA treatment improved secondary efficacy measures, regardless of HeFH status (Table). TEAE incidence was higher in patients with HeFH (BA: 81.6%; placebo: 91.7%) vs those without HeFH (BA: 76.1%; placebo: 76.1%), but was not increased with BA treatment relative to placebo.

duell et al_eas20_bainhefh_table.jpg

Conclusions

BA significantly lowered LDL-C in patients with HeFH receiving background LLT and did not increase the risk of TEAEs compared with placebo.

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