Publications by authors named "Matteo Pedrelli"

23 Publications

  • Page 1 of 1

Persistent organic pollutants and the size of ovarian reserve in reproductive-aged women.

Environ Int 2021 May 1;155:106589. Epub 2021 May 1.

Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Electronic address:

Industrial chemicals such as persistent organic pollutants (POPs) have been associated with reduced fertility in women, including longer time-to-pregnancy (TTP), higher odds for infertility, and earlier reproductive senescence. Fertility is highly dependent on the ovarian reserve, which is composed of a prenatally determined stock of non-growing follicles. The quantity and quality of the follicles decline with age, thereby eventually leading to menopause. In the clinical setting, assessing ovarian reserve directly through the histological analysis of follicular density in ovaries is not practical. Therefore, surrogate markers of ovarian reserve, such as serum anti-Müllerian hormone (AMH) are typically used. Here, we studied associations between chemical exposure and ovarian reserve in a cohort of pregnant women undergoing elective caesarean section (n = 145) in Stockholm, Sweden. Full data (histological, clinical, serum) were available for 50 women. We estimated the size of the reserve both directly by determining the density of follicles in ovarian cortical tissue samples, and indirectly by measuring AMH in associated serum samples. Concentrations of 9 organochlorine pesticides (OCPs), 10 polychlorinated biphenyls (PCBs), 3 polybrominated diphenylethers (PBDEs) and 9 perfluoroalkyl substances (PFAS) were determined in serum, and clinical data were retrieved from electronic medical records. Healthy follicle densities (median 0, range 0-193 follicles/mm) and AMH levels (median 2.33 ng/mL, range 0.1-14.8 ng/mL) varied substantially. AMH correlated with the density of growing follicles. Twenty-three chemicals detected in more than half of the samples were included in the analyses. None of the chemicals, alone or as a mixture, correlated with AMH, growing or atretic follicles. However, HCB, transnonachlor, PCBs 74 and 99 were associated with decreased non-growing follicle densities. HCB and transnonachlor were also negatively associated with healthy follicle density. Further, mixture of lipophilic POPs (PBDE 99, p,p'-DDE, and PCB 187) was associated with lower non-growing follicle densities. In addition, exposure to HCB, p,p'-DDE, and mixture of OCPs were significantly associated with higher odds of infertility. The results suggest that exposure to chemicals may reduce the size of ovarian reserve in humans, and strongly encourage to study mechanisms behind POP-associated infertility in women in more detail.
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http://dx.doi.org/10.1016/j.envint.2021.106589DOI Listing
May 2021

Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos).

J Lipid Res 2021 Mar 11;62:100065. Epub 2021 Mar 11.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Translational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Electronic address:

Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.
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http://dx.doi.org/10.1016/j.jlr.2021.100065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131316PMC
March 2021

Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease.

JCI Insight 2020 12 17;5(24). Epub 2020 Dec 17.

Department of Chemistry and Molecular Biology and.

Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.
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http://dx.doi.org/10.1172/jci.insight.140483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819747PMC
December 2020

Lack of RAC1 in macrophages protects against atherosclerosis.

PLoS One 2020 17;15(9):e0239284. Epub 2020 Sep 17.

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

The Rho GTPase RAC1 is an important regulator of cytoskeletal dynamics, but the role of macrophage-specific RAC1 has not been explored during atherogenesis. We analyzed RAC1 expression in human carotid atherosclerotic plaques using immunofluorescence and found higher macrophage RAC1 expression in advanced plaques compared with intermediate human atherosclerotic plaques. We then produced mice with Rac1-deficient macrophages by breeding conditional floxed Rac1 mice (Rac1fl/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis was studied in vivo by infecting Rac1fl/fl and Rac1fl/fl/LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Rac1fl/fl/LC macrophages secreted lower levels of IL-6 and TNF-α and exhibited reduced foam cell formation and lipid uptake. The deficiency of Rac1 in macrophages reduced the size of aortic atherosclerotic plaques in AdPCSK9-infected Rac1fl/fl/LC mice. Compare with controls, intima/media ratios, the size of necrotic cores, and numbers of CD68-positive macrophages in atherosclerotic plaques were reduced in Rac1-deficient mice. Moreover, we found that RAC1 interacts with actin-binding filamin A. Macrophages expressed increased RAC1 levels in advanced human atherosclerosis. Genetic inactivation of RAC1 impaired macrophage function and reduced atherosclerosis in mice, suggesting that drugs targeting RAC1 may be useful in the treatment of atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239284PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498073PMC
November 2020

Enzymatic Quantification of Liver Lipids After Folch Extraction.

Methods Mol Biol 2020 ;2164:101-108

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

The determination of the lipid content in liver offers the potential to investigate metabolic alterations in different research contexts. Here, we describe a method to determine cholesterol, triglycerides, and phospholipids in liver samples based on total lipid isolation by a 2:1 chloroform-methanol mixture (Folch extraction) and specific enzymatic colorimetric microassays in plate.
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http://dx.doi.org/10.1007/978-1-0716-0704-6_11DOI Listing
March 2021

The PPAR pan-agonist tetradecylthioacetic acid promotes redistribution of plasma cholesterol towards large HDL.

PLoS One 2020 16;15(3):e0229322. Epub 2020 Mar 16.

Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.

Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the β-position. This modification renders TTA unable to undergo complete β-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075573PMC
June 2020

Generation of new hepatocyte-like in vitro models better resembling human lipid metabolism.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 06 11;1865(6):158659. Epub 2020 Feb 11.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Patient Area Nephrology and Endocrinology, Inflammation and Infection Theme, Karolinska University Hospital, Stockholm, Sweden; Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address:

In contrast to human hepatocytes in vivo, which solely express acyl-coenzyme A:cholesterol acyltransferase (ACAT) 2, both ACAT1 and ACAT2 (encoded by SOAT1 and SOAT2) are expressed in primary human hepatocytes and in human hepatoma cell lines. Here, we aimed to create hepatocyte-like cells expressing the ACAT2, but not the ACAT1, protein to generate a model that - at least in this regard - resembles the human condition in vivo and to assess the effects on lipid metabolism. Using the Clustered Regularly Interspaced Short Palindromic Repeats technology, we knocked out SOAT1 in HepG2 and Huh7.5 cells. The wild type and SOAT2-only-cells were cultured with fetal bovine or human serum and the effects on lipoprotein and lipid metabolism were studied. In SOAT2-only-HepG2 cells, increased levels of cholesterol, triglycerides, apolipoprotein B and lipoprotein(a) in the cell media were detected; this was likely dependent of the increased expression of key genes involved in lipid metabolism (e.g. MTP, APOB, HMGCR, LDLR, ACACA, and DGAT2). Opposite effects were observed in SOAT2-only-Huh7.5 cells. Our study shows that the expression of SOAT1 in hepatocyte-like cells contributes to the distorted phenotype observed in HepG2 and Huh7.5 cells. As not only parameters of lipoprotein and lipid metabolism but also some markers of differentiation/maturation increase in the SOAT2-only-HepG2 cells cultured with HS, this cellular model represent an improved model for studies of lipid metabolism.
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http://dx.doi.org/10.1016/j.bbalip.2020.158659DOI Listing
June 2020

Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans.

Hepatology 2020 08 23;72(2):656-670. Epub 2020 Mar 23.

Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Stockholm, Sweden.

Background And Aims: Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences.

Approach And Results: Fah , Rag2 , and Il2rg knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level.

Conclusions: LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.
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http://dx.doi.org/10.1002/hep.31052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496592PMC
August 2020

Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα.

Nat Commun 2019 04 11;10(1):1684. Epub 2019 Apr 11.

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14157, Sweden.

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.
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http://dx.doi.org/10.1038/s41467-019-09524-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459876PMC
April 2019

Effects on hepatic lipid metabolism in human hepatoma cells following overexpression of TGFβ induced factor homeobox 1 or 2.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 05 27;1864(5):756-762. Epub 2019 Feb 27.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address:

Transforming growth factor β induced factor homeobox (TGIF) 1 and 2 are two transcriptional repressors. Although TGIF1 has been found to be involved in lipid metabolism, no studies have yet investigated the role of TGIF2 in hepatic lipid metabolism. Here we aim to investigate effects on hepatic lipid metabolism following overexpression of the human and mouse TGIF1 and TGIF2 protein. We used modified mRNA molecules to transiently enhance the expression of these proteins in human hepatoma cells. We found all the mRNA molecules to be translated, except the one for human TGIF1. Transient transfection with the mouse TGIF1 mRNA molecules lowered levels of cholesterol (p < 0.001), triglycerides (p < 0.001), and apolipoprotein B (p < 0.05) in the cell media by ~40%, along with the mRNA levels of some key genes involved in lipid metabolism. In contrast, limited effects on these parameters were observed following transient transfection with the human and mouse TGIF2 mRNA molecules. To enable investigation of the effects following enhanced expression of the human TGIF1 protein, we stably overexpressed this protein in human hepatoma cells. In line with the above findings, we found cells stably overexpressing the human TGIF1 protein had lower levels of cholesterol (p < 0.05), triglycerides (p < 0.05) and apolipoprotein B (p < 0.05) in the cell media by ~30%. Hence, transient and stable overexpression of the TGIF1 protein appears to lead to an advantageous lipid profile.
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http://dx.doi.org/10.1016/j.bbalip.2019.02.009DOI Listing
May 2019

Sex-specific lipid molecular signatures in obesity-associated metabolic dysfunctions revealed by lipidomic characterization in ob/ob mouse.

Biol Sex Differ 2019 02 26;10(1):11. Epub 2019 Feb 26.

Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.

The response to overfeeding is sex dependent, and metabolic syndrome is more likely associated to obesity in men or postmenopausal women than in young fertile women. We hypothesized that obesity-induced metabolic syndrome is sex dependent due to a sex-specific regulation of the fatty acid (FA) synthesis pathways in liver and white adipose depots. We aimed to identify distinctive molecular signatures between sexes using a lipidomics approach to characterize lipid species in liver, perigonadal adipose tissue, and inguinal adipose tissue and correlate them to the physiopathological responses observed. Males had less total fat but lower subcutaneous on visceral fat ratio together with higher liver weight and higher liver and serum triglyceride (TG) levels. Males were insulin resistant compared to females. Fatty acid (FA) and TG profiles differed between sexes in both fat pads, with longer chain FAs and TGs in males compared to that in females. Remarkably, hepatic phospholipid composition was sex dependent with more abundant lipotoxic FAs in males than in females. This may contribute to the sexual dimorphism in response to obesity towards more metaflammation in males. Our work presents an exhaustive novel description of a sex-specific lipid signature in the pathophysiology of metabolic disorders associated with obesity in ob/ob mice. These data could settle the basis for future pharmacological treatment in obesity.
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http://dx.doi.org/10.1186/s13293-019-0225-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390380PMC
February 2019

ERβ activation in obesity improves whole body metabolism via adipose tissue function and enhanced mitochondria biogenesis.

Mol Cell Endocrinol 2019 01 17;479:147-158. Epub 2018 Oct 17.

Department of Biosciences and Nutrition Huddinge, Karolinska Institutet, Sweden; Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signalling, University of Houston, Houston, TX, USA.

Objective: Estrogens play a key role in the distribution of adipose tissue and have their action by binding to both estrogen receptors (ER), α and β. Although ERβ has a role in the energy metabolism, limited data of the physiological mechanism and metabolic response involved in the pharmacological activation of ERβ is available.

Methods: For clinical relevance, non-ovariectomized female mice were subjected to high fat diet together with pharmacological (DIP - 4-(2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl)phenol) interventions to ERβ selective activation. The physiological mechanism was assessed in vivo by magnetic resonance imaging and spectroscopy, and oral glucose and intraperitoneal insulin tolerance test before and after DIP treatment. Liver and adipose tissue metabolic response was measured in HFD + vehicle and HFD + DIP by stable isotope, RNA sequencing and protein content.

Results: HFD-fed females treated with DIP had a tissue-specific response towards ERβ selective activation. The metabolic profile showed an improved fasting glucose level, insulin sensitivity and reduced liver steatosis.

Conclusions: Our data demonstrate that selective activation of ERβ exerts a tissue-specific activity which promotes a beneficial effect on whole body metabolic response to obesity.
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http://dx.doi.org/10.1016/j.mce.2018.10.007DOI Listing
January 2019

STK25 Regulates Cardiovascular Disease Progression in a Mouse Model of Hypercholesterolemia.

Arterioscler Thromb Vasc Biol 2018 08;38(8):1723-1737

From the Lundberg Laboratory for Diabetes Research (E.C., E.M., E.N.-D., J.H., M.M.).

Objective- Recent cohort studies have shown that nonalcoholic fatty liver disease (NAFLD), and especially nonalcoholic steatohepatitis (NASH), associate with atherosclerosis and cardiovascular disease, independently of conventional cardiometabolic risk factors. However, the mechanisms underlying the pathophysiological link between NAFLD/NASH and cardiovascular disease still remain unclear. Our previous studies have identified STK25 (serine/threonine protein kinase 25) as a critical determinant in ectopic lipid storage, meta-inflammation, and progression of NAFLD/NASH. The aim of this study was to assess whether STK25 is also one of the mediators in the complex molecular network controlling the cardiovascular disease risk. Approach and Results- Atherosclerosis was induced in Stk25 knockout and transgenic mice, and their wild-type littermates, by gene transfer of gain-of-function mutant of PCSK9 (proprotein convertase subtilisin/kexin type 9), which induces the downregulation of hepatic LDLR (low-density lipoprotein receptor), combined with an atherogenic western-type diet. We found that Stk25 mice displayed reduced atherosclerosis lesion area as well as decreased lipid accumulation, macrophage infiltration, collagen formation, and oxidative stress in aortic lesions compared with wild-type littermates, independently from alterations in dyslipidemia. Reciprocally, Stk25 transgenic mice presented aggravated plaque formation and maturation compared with wild-type littermates despite similar levels of fasting plasma cholesterol. We also found that STK25 protein was expressed in all layers of the aorta, suggesting a possible direct role in cardiovascular disease. Conclusions- This study provides the first evidence that STK25 plays a critical role in regulation of cardiovascular disease risk and suggests that pharmacological inhibition of STK25 function may provide new possibilities for prevention/treatment of atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.118.311241DOI Listing
August 2018

Lipids around the Clock: Focus on Circadian Rhythms and Lipid Metabolism.

Biology (Basel) 2015 Feb 5;4(1):104-32. Epub 2015 Feb 5.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, 14186, Sweden.

Disorders of lipid and lipoprotein metabolism and transport are responsible for the development of a large spectrum of pathologies, ranging from cardiovascular diseases, to metabolic syndrome, even to tumour development. Recently, a deeper knowledge of the molecular mechanisms that control our biological clock and circadian rhythms has been achieved. From these studies it has clearly emerged how the molecular clock tightly regulates every aspect of our lives, including our metabolism. This review analyses the organisation and functioning of the circadian clock and its relevance in the regulation of physiological processes. We also describe metabolism and transport of lipids and lipoproteins as an essential aspect for our health, and we will focus on how the circadian clock and lipid metabolism are greatly interconnected. Finally, we discuss how a deeper knowledge of this relationship might be useful to improve the recent spread of metabolic diseases.
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http://dx.doi.org/10.3390/biology4010104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381220PMC
February 2015

Hepatic ACAT2 knock down increases ABCA1 and modifies HDL metabolism in mice.

PLoS One 2014 2;9(4):e93552. Epub 2014 Apr 2.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Molecular Nutrition Unit, Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Objectives: ACAT2 is the exclusive cholesterol-esterifying enzyme in hepatocytes and enterocytes. Hepatic ABCA1 transfers unesterified cholesterol (UC) to apoAI, thus generating HDL. By changing the hepatic UC pool available for ABCA1, ACAT2 may affect HDL metabolism. The aim of this study was to reveal whether hepatic ACAT2 influences HDL metabolism.

Design: WT and LXRα/β double knockout (DOKO) mice were fed a western-type diet for 8 weeks. Animals were i.p. injected with an antisense oligonucleotide targeted to hepatic ACAT2 (ASO6), or with an ASO control. Injections started 4 weeks after, or concomitantly with, the beginning of the diet.

Results: ASO6 reduced liver cholesteryl esters, while not inducing UC accumulation. ASO6 increased hepatic ABCA1 protein independently of the diet conditions. ASO6 affected HDL lipids (increased UC) only in DOKO, while it increased apoE-containing HDL in both genotypes. In WT mice ASO6 led to the appearance of large HDL enriched in apoAI and apoE.

Conclusions: The use of ASO6 revealed a new pathway by which the liver may contribute to HDL metabolism in mice. ACAT2 seems to be a hepatic player affecting the cholesterol fluxes fated to VLDL or to HDL, the latter via up-regulation of ABCA1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973598PMC
February 2015

Fasting-induced FGF21 is repressed by LXR activation via recruitment of an HDAC3 corepressor complex in mice.

Mol Endocrinol 2012 Dec 16;26(12):1980-90. Epub 2012 Oct 16.

Department of Biosciences and Nutrition and Center for Biosciences at Novum, Karolinska Institute, S-141 83 Huddinge, Sweden.

The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα(-/-), and LXRβ(-/-) mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα(-/-) and LXRβ(-/-) mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting.
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http://dx.doi.org/10.1210/me.2012-1151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416953PMC
December 2012

Liver X receptors regulate de novo lipogenesis in a tissue-specific manner in C57BL/6 female mice.

Am J Physiol Endocrinol Metab 2011 Jul 26;301(1):E210-22. Epub 2011 Apr 26.

Department of Biosciences and Nutrition and Center for Biosciences at NOVUM, Karolinska Institutet, Lipid Laboratory, Huddinge, Sweden.

The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRαβ(-/-) mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRαβ(-/-) mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRαβ(-/-) mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRαβ(-/-) mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from Vo(2) and Vco(2) was significantly higher in LXRαβ(-/-) than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRαβ(-/-) mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRαβ(-/-) mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRαβ(-/-) mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRαβ(-/-) mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development.
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http://dx.doi.org/10.1152/ajpendo.00541.2010DOI Listing
July 2011

Role of thyroid receptor β in lipid metabolism.

Biochim Biophys Acta 2011 Aug 29;1812(8):929-37. Epub 2010 Dec 29.

Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.

Thyroid hormones (THs) exert their actions by binding to thyroid hormone receptors (TRs) and thereby affect tissue differentiation, development, and metabolism in most tissues. TH-deficiency creates a less favorable lipid profile (e.g. increased plasma cholesterol levels), whereas TH-excess is associated with both positive (e.g. reduced plasma cholesterol levels) and negative (e.g. increased heart rate) effects. TRs are encoded by two genes, THRA and THRB, which, by alternative splicing, generate several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). TRα, the major TR in the heart, is crucial for heart rate and for cardiac contractility and relaxation, whereas TRβ1, the major TR in the liver, is important for lipid metabolism. Selective modulation of TRβ1 is thus considered as a potential therapeutic target to treat dyslipidemia without cardiac side effects. Several selective TH analogs have been tested in preclinical studies with promising results, but only a few of these compounds have so far been tested in clinical studies. This review focuses on the role of THs, TRs, and selective and non-selective TH analogs in lipid metabolism. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
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http://dx.doi.org/10.1016/j.bbadis.2010.12.019DOI Listing
August 2011

Thyroid hormones and thyroid hormone receptors: effects of thyromimetics on reverse cholesterol transport.

World J Gastroenterol 2010 Dec;16(47):5958-64

Division of Clinical Chemistry, Department of Laboratory Medicine, Molecular Nutrition Unit, Karolinska Institutet at Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden.

Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, development, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TRβ1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TRβ1-modulating thyromimetics on RCT in various animal models and in humans.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3007105PMC
http://dx.doi.org/10.3748/wjg.v16.i47.5958DOI Listing
December 2010

Macrophage, but not systemic, apolipoprotein E is necessary for macrophage reverse cholesterol transport in vivo.

Arterioscler Thromb Vasc Biol 2011 Jan 21;31(1):74-80. Epub 2010 Oct 21.

Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università di Parma, 43100 Parma, Italy.

Objective: To assess the role of apolipoprotein (apo) E in macrophage reverse cholesterol transport (RCT) in vivo.

Methods And Results: ApoE exerts an antiatherosclerotic activity by regulating lipoprotein metabolism and promoting cell cholesterol efflux. We discriminated between macrophage and systemic apoE contribution using an assay of macrophage RCT in mice. The complete absence of apoE lead to an overall impairment of the process and, similarly, the absence of apoE exclusively in macrophages resulted in the reduction of cholesterol mobilization from macrophages to plasma, liver, and feces. Conversely, expression of apoE in macrophages is sufficient to promote normal RCT even in apoE-deficient mice. The mechanisms accounting for these results were investigated by evaluating the first step of RCT (ie, cholesterol efflux from cells). Macrophages isolated from apoE-deficient mice showed a reduced ability to release cholesterol into the culture medium, whereas the apoB-depleted plasma from apoE-deficient and healthy mice possessed a similar capacity to promote cellular lipid release from cultured macrophages.

Conclusions: Our data demonstrate, for the first time to our knowledge, that apoE significantly contributes to macrophage RCT in vivo and that this role is fully attributable to apoE expressed in macrophages.
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http://dx.doi.org/10.1161/ATVBAHA.110.213892DOI Listing
January 2011

Manidipine reduces pro-inflammatory cytokines secretion in human endothelial cells and macrophages.

Pharmacol Res 2010 Sep 27;62(3):265-70. Epub 2010 Mar 27.

Department of Pharmacological and Biological Sciences, and Applied Chemistries, University of Parma, 43100 Parma, Italy.

The dihydropyridine calcium antagonists (DHP-CA), commonly used for the treatment of hypertension, may exert antiatherosclerotic activity independent of the blood-pressure lowering properties. The aim of this study was to evaluate the effect in cell culture of the third generation DHP-CA Manidipine on the release of interleukin-6 (IL-6) and interleukin-8 (IL-8) from human endothelial cells and human macrophages, in response to different pro-inflammatory signals. In endothelial cells, incubation with acetylated LDL (acLDL), oxidized LDL (oxLDL) or tumor necrosis factor-alpha (TNF-alpha), increased the release of IL-6 from 50% to 100%. Manidipine 1-5 microM was able to completely inhibit IL-6 production induced by either of these factors. In these cells TNF-alpha increased by about 4 times the secretion of IL-8 and Manidipine 5 microM reduced the amount of IL-8 in the culture media by about 40%. In human macrophages THP-1, treatment with different cytokines was able to stimulate by about 3-folds the release of IL-6 and Manidipine 1 microM showed a 25% inhibition on TNF-alpha-induced IL-6 secretion. In these cells, a combined treatment with multiple cytokines, induced IL-6 production of about 6-folds and Manidipine was able to reduce such inflammatory response by 30%. Our experiments highlighted the anti-inflammatory properties of Manidipine in either human endothelial cells or macrophages. The mechanism by which Manidipine exert this effect is not related to its blocking activity on calcium channels and it involves an inhibition of NF-kappaB activation, that, in analogy with what is observed for other DHP-CA, may be related to the high lipophilicity and the antioxidant activity of this compound.
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http://dx.doi.org/10.1016/j.phrs.2010.03.004DOI Listing
September 2010

Functional LCAT is not required for macrophage cholesterol efflux to human serum.

Atherosclerosis 2009 May 6;204(1):141-6. Epub 2008 Sep 6.

Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano, Milano, Italy.

Objectives: To evaluate the capacity of serum from carriers of LCAT gene mutations to promote cell cholesterol efflux through the ABCA1, ABCG1, and SR-BI pathways.

Methods: Serum was obtained from 41 carriers of mutant LCAT alleles (14 carriers of two mutant LCAT alleles and 27 heterozygotes) and 10 non-carrier relatives (controls). The capacity of serum to promote cholesterol efflux was tested in pathway-specific cell models.

Results: LCAT deficient sera were significantly more efficient than control sera in promoting cell cholesterol efflux via ABCA1 (3.1+/-0.3% for carriers of two mutant LCAT alleles and 2.6+/-0.2% for heterozygotes vs. 1.5+/-0.4% for controls), and less efficient in promoting ABCG1- and SR-BI-mediated cholesterol efflux. The enhanced capacity of LCAT deficient serum for ABCA1 efflux is explained by the increased content of prebeta-HDL, as indicated by the significant positive correlation between ABCA1 efflux and serum prebeta-HDL content (R=0.468, P<0.001). Moreover, chymase treatment of LCAT deficient serum selectively degraded prebeta-HDL and completely abolished ABCA1 efflux. Despite the remarkable reductions in serum HDL levels, LCAT deficient sera were as effective as control sera in removing mass cholesterol from cholesterol-loaded macrophages.

Conclusions: Serum from carriers of LCAT gene mutations has the same capacity of control serum to decrease the cholesterol content of cholesterol-loaded macrophages due to a greater cholesterol efflux capacity via ABCA1.
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http://dx.doi.org/10.1016/j.atherosclerosis.2008.08.038DOI Listing
May 2009

The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential.

J Lipid Res 2008 May 5;49(5):954-60. Epub 2008 Feb 5.

Department of Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, 43100 Parma, Italy.

The liver X receptors (LXRs) have been shown to affect lipoprotein plasma profile, lipid metabolism, and reverse cholesterol transport (RCT). In the present study, we investigated whether a short-term administration of the synthetic LXR agonist T0901317 (T0) to mice may affect RCT by modulating the capacity of plasma to promote cellular lipid efflux. Consistent with previous data, the pharmacological treatment of mice caused a significant increase of macrophage-derived [3H]cholesterol content in plasma, liver, and feces and resulted in improved capacity of plasma to promote cellular cholesterol release through passive diffusion and scavenger receptor class B type I (SR-BI)-mediated mechanisms. Differently, plasma from treated mice possessed similar or reduced capacity to drive lipid efflux via ABCA1. Consistent with these data, the analysis of plasma HDL fractions revealed that T0 caused the formation of larger, lipid-enriched particles. These results suggest that T0 promotes in vivo RCT from macrophages at least in part by inducing an enrichment of those HDL subclasses that increase plasma capacity to promote cholesterol efflux by passive diffusion and SR-BI-mediated mechanisms.
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http://dx.doi.org/10.1194/jlr.M700254-JLR200DOI Listing
May 2008