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Article ; Online: Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis.

Carlsson, Björn / Lindén, Daniel / Brolén, Gabriella / Liljeblad, Mathias / Bjursell, Mikael / Romeo, Stefano / Loomba, Rohit

Alimentary pharmacology & therapeutics

2020 Volume 51, Issue 12, Page(s) 1305–1320

Abstract: Background: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases ... ...

Abstract	Background: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. Aims: To review NASH genetics and discuss the potential for precision medicine approaches to treatment. Method: PubMed search and inclusion of relevant literature. Results: Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. Conclusion: The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
MeSH term(s)	Alleles ; Carcinoma, Hepatocellular/complications ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/therapy ; Disease Progression ; Genetic Predisposition to Disease ; Genetic Testing/methods ; Genetic Testing/trends ; Humans ; Liver Neoplasms/complications ; Liver Neoplasms/genetics ; Liver Neoplasms/therapy ; Non-alcoholic Fatty Liver Disease/diagnosis ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/pathology ; Non-alcoholic Fatty Liver Disease/therapy ; Polymorphism, Single Nucleotide ; Precision Medicine/methods ; Precision Medicine/trends ; Prognosis
Language	English
Publishing date	2020-05-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639012-2
ISSN	1365-2036 ; 0269-2813 ; 0953-0673
ISSN (online)	1365-2036
ISSN	0269-2813 ; 0953-0673
DOI	10.1111/apt.15738
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Article ; Online: Deletion of Gpr55 Results in Subtle Effects on Energy Metabolism, Motor Activity and Thermal Pain Sensation.

Bjursell, Mikael / Ryberg, Erik / Wu, Tingting / Greasley, Peter J / Bohlooly-Y, Mohammad / Hjorth, Stephan

PloS one

2016 Volume 11, Issue 12, Page(s) e0167965

Abstract: The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed ... ...

Abstract	The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part. However, Gpr55 KO animals displayed an intriguing nocturnal pattern of motor activity and energy expenditure (EE). During the initial 6 hours of the night, motor activity was significantly elevated without any significant effect observed in EE. Interestingly, during the last 6 hours of the night motor activity was similar but EE was significantly decreased in the Gpr55 KO mice. No significant difference in motor activity was detected during daytime, but EE was lower in the Gpr55 KO compared to WT mice. The aforementioned patterns were not associated with alterations in energy intake, daytime core body temperature, body weight (BW) or composition, although a non-significant tendency to increased adiposity was seen in Gpr55 KO compared to WT mice. Detailed analyses of daytime activity in the Open Field paradigm unveiled lower horizontal activity and rearing time for the Gpr55 KO mice. Moreover, the Gpr55 KO mice displayed significantly faster reaction time in the tail flick test, indicative of thermal hyperalgesia. The BW-decreasing effect of rimonabant in mice on long-term cafeteria diet did not differ between Gpr55 KO and WT mice. In conclusion, Gpr55 deficiency is associated with subtle effects on diurnal/nocturnal EE and motor activity behaviours but does not appear per se critically required for overall metabolism or behaviours.
MeSH term(s)	Animals ; Behavior, Animal ; Body Temperature ; Calorimetry ; Cannabinoid Receptor Antagonists/metabolism ; Diet, High-Fat ; Energy Metabolism/genetics ; Gene Deletion ; Longitudinal Studies ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity/genetics ; Pain/genetics ; Pain/metabolism ; Piperidines/metabolism ; Pyrazoles/metabolism ; Receptors, Cannabinoid/deficiency ; Receptors, Cannabinoid/genetics ; Receptors, Cannabinoid/metabolism ; Thermosensing/genetics
Chemical Substances	Cannabinoid Receptor Antagonists ; GPR55 protein, mouse ; Piperidines ; Pyrazoles ; Receptors, Cannabinoid ; rimonabant (RML78EN3XE)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0167965
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Article ; Online: Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects.

Rodriguez-Cuenca, Sergio / Lelliot, Christopher J / Campbell, Mark / Peddinti, Gopal / Martinez-Uña, Maite / Ingvorsen, Camilla / Dias, Ana Rita / Relat, Joana / Mora, Silvia / Hyötyläinen, Tuulia / Zorzano, Antonio / Orešič, Matej / Bjursell, Mikael / Bohlooly-Y, Mohammad / Lindén, Daniel / Vidal-Puig, Antonio

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2021 Volume 35, Issue 9, Page(s) e21752

Abstract: Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic ... ...

Abstract	Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.
MeSH term(s)	Adipose Tissue/metabolism ; Aging/genetics ; Animals ; Disease Models, Animal ; Energy Metabolism/genetics ; Heterozygote ; Insulin Resistance/genetics ; Male ; Mice ; Mitochondria/genetics ; Nuclear Proteins/genetics ; Obesity/genetics ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics ; Thermogenesis/genetics ; Transcription Factors/genetics ; Transcriptome/genetics
Chemical Substances	Nuclear Proteins ; Ppargc1b protein, mouse ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Transcription Factors
Language	English
Publishing date	2021-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202100262RR
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Lingonberries alter the gut microbiota and prevent low-grade inflammation in high-fat diet fed mice.

Heyman-Lindén, Lovisa / Kotowska, Dorota / Sand, Elin / Bjursell, Mikael / Plaza, Merichel / Turner, Charlotta / Holm, Cecilia / Fåk, Frida / Berger, Karin

Food & nutrition research

2016 Volume 60, Page(s) 29993

Abstract: Background: The gut microbiota plays an important role in the development of obesity and obesity-associated impairments such as low-grade inflammation. Lingonberries have been shown to prevent diet-induced obesity and low-grade inflammation. However, it ...

Abstract	Background: The gut microbiota plays an important role in the development of obesity and obesity-associated impairments such as low-grade inflammation. Lingonberries have been shown to prevent diet-induced obesity and low-grade inflammation. However, it is not known whether the effect of lingonberry supplementation is related to modifications of the gut microbiota. The aim of the present study was to describe whether consumption of different batches of lingonberries alters the composition of the gut microbiota, which could be relevant for the protective effect against high fat (HF)-induced metabolic alterations. Methods: Three groups of C57BL/6J mice were fed HF diet with or without a supplement of 20% lingonberries from two different batches (Lingon1 and Lingon2) during 11 weeks. The composition and functionality of the cecal microbiota were assessed by 16S rRNA sequencing and PICRUSt. In addition, parameters related to obesity, insulin sensitivity, hepatic steatosis, inflammation and gut barrier function were examined. Results: HF-induced obesity was only prevented by the Lingon1 diet, whereas both batches of lingonberries reduced plasma levels of markers of inflammation and endotoxemia (SAA and LBP) as well as modified the composition and functionality of the gut microbiota, compared to the HF control group. The relative abundance of Akkermansia and Faecalibacterium, genera associated with healthy gut mucosa and anti-inflammation, was found to increase in response to lingonberry intake. Conclusions: Our results show that supplementation with lingonberries to an HF diet prevents low-grade inflammation and is associated with significant changes of the microbiota composition. Notably, the anti-inflammatory properties of lingonberries seem to be independent of effects on body weight gain.
Language	English
Publishing date	2016-04-27
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	2418338-6
ISSN	1654-661X ; 1654-661X ; 1654-6628
ISSN (online)	1654-661X
ISSN	1654-661X ; 1654-6628
DOI	10.3402/fnr.v60.29993
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Article: Lingonberries alter the gut microbiota and prevent low-grade inflammation in high-fat diet fed mice

Heyman-Lindén, Lovisa / Kotowska, Dorota / Sand, Elin / Bjursell, Mikael / Plaza, Merichel / Turner, Charlotta / Holm, Cecilia / Fåk, Frida / Berger, Karin

Food & nutrition research. 2016 Jan. 1, v. 60, no. 1

2016

Abstract: The gut microbiota plays an important role in the development of obesity and obesity-associated impairments such as low-grade inflammation. Lingonberries have been shown to prevent diet-induced obesity and low-grade inflammation. However, it is not known ...

Abstract	The gut microbiota plays an important role in the development of obesity and obesity-associated impairments such as low-grade inflammation. Lingonberries have been shown to prevent diet-induced obesity and low-grade inflammation. However, it is not known whether the effect of lingonberry supplementation is related to modifications of the gut microbiota. The aim of the present study was to describe whether consumption of different batches of lingonberries alters the composition of the gut microbiota, which could be relevant for the protective effect against high fat (HF)-induced metabolic alterations. Three groups of C57BL/6J mice were fed HF diet with or without a supplement of 20% lingonberries from two different batches (Lingon1 and Lingon2) during 11 weeks. The composition and functionality of the cecal microbiota were assessed by 16S rRNA sequencing and PICRUSt. In addition, parameters related to obesity, insulin sensitivity, hepatic steatosis, inflammation and gut barrier function were examined. HF-induced obesity was only prevented by the Lingon1 diet, whereas both batches of lingonberries reduced plasma levels of markers of inflammation and endotoxemia (SAA and LBP) as well as modified the composition and functionality of the gut microbiota, compared to the HF control group. The relative abundance of Akkermansia and Faecalibacterium, genera associated with healthy gut mucosa and anti-inflammation, was found to increase in response to lingonberry intake. Our results show that supplementation with lingonberries to an HF diet prevents low-grade inflammation and is associated with significant changes of the microbiota composition. Notably, the anti-inflammatory properties of lingonberries seem to be independent of effects on body weight gain.
Keywords	Vaccinium vitis-idaea ; absorption barrier ; anti-inflammatory activity ; body weight changes ; digestive tract mucosa ; endotoxemia ; fatty liver ; high fat diet ; inflammation ; insulin resistance ; intestinal microorganisms ; mice ; obesity ; protective effect ; ribosomal RNA ; sequence analysis
Language	English
Dates of publication	2016-0101
Publishing place	Taylor & Francis
Document type	Article
ZDB-ID	2418338-6
ISSN	1654-661X ; 1654-6628
ISSN (online)	1654-661X
ISSN	1654-6628
DOI	10.3402/fnr.v60.29993
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Therapeutic Genome Editing With CRISPR/Cas9 in a Humanized Mouse Model Ameliorates α1-antitrypsin Deficiency Phenotype.

Bjursell, Mikael / Porritt, Michelle J / Ericson, Elke / Taheri-Ghahfarokhi, Amir / Clausen, Maryam / Magnusson, Lisa / Admyre, Therese / Nitsch, Roberto / Mayr, Lorenz / Aasehaug, Leif / Seeliger, Frank / Maresca, Marcello / Bohlooly-Y, Mohammad / Wiseman, John

EBioMedicine

2018 Volume 29, Page(s) 104–111

Abstract: α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene ... ...

Abstract	α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Our single dose therapeutic gene editing approach completely reverted the phenotype associated with the PiZ mutation, including circulating transaminase and human AAT (hAAT) protein levels, liver fibrosis and protein aggregation. Furthermore, liver histology was significantly improved regarding inflammation and overall morphology in hSERPINA1 gene edited PiZ mice. Genomic analysis confirmed significant disruption to the hSERPINA1 transgene resulting in a reduction of hAAT protein levels and quantitative mRNA analysis showed a reduction in fibrosis and hepatocyte proliferation as a result of editing. Our findings indicate that therapeutic gene editing in hepatocytes is possible in an AATD mouse model.
MeSH term(s)	Adenoviridae/genetics ; Animals ; CRISPR-Cas Systems ; Cell Proliferation ; Disease Models, Animal ; Gene Editing ; Gene Expression ; Genetic Vectors/genetics ; Humans ; Mice ; Mice, Transgenic ; Phenotype ; Transduction, Genetic ; Transgenes ; alpha 1-Antitrypsin/blood ; alpha 1-Antitrypsin/genetics ; alpha 1-Antitrypsin/metabolism ; alpha 1-Antitrypsin Deficiency/genetics ; alpha 1-Antitrypsin Deficiency/metabolism ; alpha 1-Antitrypsin Deficiency/pathology ; alpha 1-Antitrypsin Deficiency/therapy
Chemical Substances	alpha 1-Antitrypsin
Language	English
Publishing date	2018-02-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2018.02.015
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Article ; Online: Cardiac-Specific Overexpression of Oxytocin Receptor Leads to Cardiomyopathy in Mice.

Jung, Christian / Wernly, Bernhard / Bjursell, Mikael / Wiseman, John / Admyre, Therese / Wikström, Johannes / Palmér, Malin / Seeliger, Frank / Lichtenauer, Michael / Franz, Marcus / Frick, Charlotte / Andersson, Ann-Katrin / Elg, Margareta / Pernow, John / Sjöquist, Per-Ove / Bohlooly-Y, Mohammad / Wang, Qing-Dong

Journal of cardiac failure

2018 Volume 24, Issue 7, Page(s) 470–478

Abstract: Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that ... ...

Abstract	Background: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that overexpress Oxtr specifically in the heart. Methods and results: Cardiac-specific overexpression of Oxtr was obtained by having the α-major histocompatibility complex promoter drive the mouse Oxtr gene (α-Mhc-Oxtr). Left ventricular (LV) function and remodeling were assessed by magnetic resonance imaging and echocardiography. In α-Mhc-Oxtr TG mice, LV ejection fraction was severely compromised at 14 weeks of age compared with wild-type (WT) littermates (25 ± 6% vs 63 ± 3%; P < .001). LV end-diastolic volume was larger in the TG mice (103 ± 6 µL vs 67 ± 5 µL; P < .001). α-Mhc-Oxtr TG animals displayed cardiac fibrosis, atrial thrombus, and increased expression of pro-fibrogenic genes. Mortality of α-Mhc-Oxtr TG animals was 45% compared with 0% (P < .0001) of WT littermates by 20 weeks of age. Most cardiomyocytes of α-Mhc-Oxtr TG animals but not WT littermates (68.0 ± 12.1% vs 5.6 ± 2.4%; P = .008) were positive in staining for nuclear factor of activated T cells (NFAT). To study if thrombin inhibitor prevents thrombus formation, a cohort of 7-week-old α-Mhc-Oxtr TG mice were treated for 12 weeks with AZD0837, a potent thrombin inhibitor. Treatment with AZD0837 reduced thrombus formation (P < .05) and tended to attenuate fibrosis and increase survival. Conclusions: Cardiac-specific overexpression of Oxtr had negative consequences on LV function and survival in mice. The present findings necessitate further studies to investigate potential adverse effects of chronic Oxt administration. We provide a possible mechanism of Oxtr overexpression leading to heart failure by nuclear factor of activated T cell signaling. The recapitulation of human heart failure and the beneficial effects of the antithrombin inhibitor render the α-Mhc-Oxtr TG mice a promising tool in drug discovery for heart failure.
MeSH term(s)	Animals ; Cardiomyopathies/diagnosis ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Disease Models, Animal ; Echocardiography ; Gene Expression Regulation ; Magnetic Resonance Imaging, Cine ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocardium/metabolism ; Myocardium/pathology ; RNA/genetics ; Real-Time Polymerase Chain Reaction ; Receptors, Oxytocin/biosynthesis ; Receptors, Oxytocin/genetics
Chemical Substances	OXTR protein, mouse ; Receptors, Oxytocin ; RNA (63231-63-0)
Language	English
Publishing date	2018-05-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	1281194-4
ISSN	1532-8414 ; 1071-9164
ISSN (online)	1532-8414
ISSN	1071-9164
DOI	10.1016/j.cardfail.2018.05.004
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Article ; Online: Effects of a novel potent melanin-concentrating hormone receptor 1 antagonist, AZD1979, on body weight homeostasis in mice and dogs.

Ploj, Karolina / Benthem, Lambertus / Kakol-Palm, Dorota / Gennemark, Peter / Andersson, Liselotte / Bjursell, Mikael / Börjesson, Jenny / Kärrberg, Lillevi / Månsson, Marianne / Antonsson, Madeleine / Johansson, Anders / Iverson, Suzanne / Carlsson, Björn / Turnbull, Andrew / Lindén, Daniel

British journal of pharmacology

2016 Volume 173, Issue 18, Page(s) 2739–2751

Abstract: Background and purpose: Melanin-concentrating hormone (MCH) is an orexigen, and while rodents express one MCH receptor (MCH1 receptor), humans, non-human primates and dogs express two MCH receptors (MCH1 and MCH2 ). MCH1 receptor antagonists have been ... ...

Abstract	Background and purpose: Melanin-concentrating hormone (MCH) is an orexigen, and while rodents express one MCH receptor (MCH1 receptor), humans, non-human primates and dogs express two MCH receptors (MCH1 and MCH2 ). MCH1 receptor antagonists have been developed for the treatment of obesity and lower body weight in rodents. However, the mechanisms for the body weight loss and whether MCH1 receptor antagonism can lower body weight in species expressing both MCH receptors are not fully understood. Experimental approach: A novel recently identified potent MCH1 receptor antagonist, AZD1979, was studied in wild type and Mchr1 knockout (KO) mice and by using pair-feeding and indirect calorimetry in diet-induced obese (DIO) mice. The effect of AZD1979 on body weight was also studied in beagle dogs. Key results: AZD1979 bound to MCH1 receptors in the CNS and dose-dependently reduced body weight in DIO mice leading to improved homeostasis model assessment-index of insulin sensitivity. AZD1979 did not affect food intake or body weight in Mchr1 KO mice demonstrating specificity for the MCH1 receptor mechanism. In DIO mice, initial AZD1979-mediated body weight loss was driven by decreased food intake, but an additional component of preserved energy expenditure was apparent in pair-feeding and indirect calorimetry studies. AZD1979 also dose-dependently reduced body weight in dogs. Conclusion and implications: AZD1979 is a novel potent MCH1 receptor antagonist that affects both food intake and energy expenditure. That AZD1979 also lowers body weight in a species expressing both MCH receptors holds promise for the use of MCH1 receptor antagonists for the treatment of human obesity.
MeSH term(s)	Animals ; Azetidines/administration & dosage ; Azetidines/chemistry ; Azetidines/pharmacology ; Body Weight/drug effects ; Dogs ; Dose-Response Relationship, Drug ; Female ; Homeostasis/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Structure ; Oxadiazoles/administration & dosage ; Oxadiazoles/chemistry ; Oxadiazoles/pharmacology ; Receptors, Somatostatin/antagonists & inhibitors ; Receptors, Somatostatin/deficiency ; Structure-Activity Relationship
Chemical Substances	AZD1979 ; Azetidines ; Mchr1 protein, mouse ; Oxadiazoles ; Receptors, Somatostatin
Language	English
Publishing date	2016-08-03
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.13548
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Article ; Online: Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice.

Lindén, Daniel / Ahnmark, Andrea / Pingitore, Piero / Ciociola, Ester / Ahlstedt, Ingela / Andréasson, Anne-Christine / Sasidharan, Kavitha / Madeyski-Bengtson, Katja / Zurek, Magdalena / Mancina, Rosellina M / Lindblom, Anna / Bjursell, Mikael / Böttcher, Gerhard / Ståhlman, Marcus / Bohlooly-Y, Mohammad / Haynes, William G / Carlsson, Björn / Graham, Mark / Lee, Richard /

Murray, Sue / Valenti, Luca / Bhanot, Sanjay / Åkerblad, Peter / Romeo, Stefano

Molecular metabolism

2019 Volume 22, Page(s) 49–61

Abstract: Objective: Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor ... ...

Abstract	Objective: Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD. Methods: We examined the effects of liver-targeted GalNAc Results: ASO-mediated silencing of Pnpla3 reduced liver steatosis (p = 0.038) in homozygous Pnpla3 148M/M knock-in mutant mice but not in wild-type littermates fed a steatogenic high-sucrose diet. In mice fed a NASH-inducing diet, ASO-mediated silencing of Pnpla3 reduced liver steatosis score and NAFLD activity score independent of the Pnpla3 genotype, while reductions in liver inflammation score (p = 0.018) and fibrosis stage (p = 0.031) were observed only in the Pnpla3 knock-in 148M/M mutant mice. These responses were accompanied by reduced liver levels of Mcp1 (p = 0.026) and Timp2 (p = 0.007) specifically in the mutant knock-in mice. This may reduce levels of chemokine attracting inflammatory cells and increase the collagenolytic activity during tissue regeneration. Conclusion: This study provides the first evidence that a Pnpla3 ASO therapy can improve all features of NAFLD, including liver fibrosis, and suppress the expression of a strong innate genetic risk factor, Pnpla3 148M, which may open up a precision medicine approach in NASH.
MeSH term(s)	Animals ; Female ; Gene Silencing ; Humans ; Lipase/genetics ; Lipase/metabolism ; Liver Cirrhosis/genetics ; Liver Cirrhosis/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/metabolism ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/metabolism ; Phospholipases A2, Calcium-Independent/genetics ; Phospholipases A2, Calcium-Independent/metabolism
Chemical Substances	Membrane Proteins ; Oligonucleotides, Antisense ; Lipase (EC 3.1.1.3) ; PNPLA3 protein, mouse (EC 3.1.1.3) ; adiponutrin, human (EC 3.1.1.3) ; Phospholipases A2, Calcium-Independent (EC 3.1.1.4)
Language	English
Publishing date	2019-02-05
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2019.01.013
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Article ; Online: In vivo genome and base editing of a human PCSK9 knock-in hypercholesterolemic mouse model.

BMC biology

2019 Volume 17, Issue 1, Page(s) 4

Abstract: Background: Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates cholesterol homeostasis, has ...

Abstract	Background: Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates cholesterol homeostasis, has recently emerged as an approach to reduce cholesterol levels. The development of humanized animal models is an important step to validate and study human drug targets, and use of genome and base editing has been proposed as a mean to target disease alleles. Results: To address the lack of validated models to test the safety and efficacy of techniques to target human PCSK9, we generated a liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI). We showed that plasma concentrations of total cholesterol were higher in hPCSK9-KI than in wildtype mice and increased with age. Treatment with evolocumab, a monoclonal antibody that targets human PCSK9, reduced cholesterol levels in hPCSK9-KI but not in wildtype mice, showing that the hypercholesterolemic phenotype was driven by overexpression of human PCSK9. CRISPR-Cas9-mediated genome editing of human PCSK9 reduced plasma levels of human and not mouse PCSK9, and in parallel reduced plasma concentrations of total cholesterol; genome editing of mouse Pcsk9 did not reduce cholesterol levels. Base editing using a guide RNA that targeted human and mouse PCSK9 reduced plasma levels of human and mouse PCSK9 and total cholesterol. In our mouse model, base editing was more precise than genome editing, and no off-target editing nor chromosomal translocations were identified. Conclusions: Here, we describe a humanized mouse model with liver-specific expression of human PCSK9 and a human-like hypercholesterolemia phenotype, and demonstrate that this mouse can be used to evaluate antibody and gene editing-based (genome and base editing) therapies to modulate the expression of human PCSK9 and reduce cholesterol levels. We predict that this mouse model will be used in the future to understand the efficacy and safety of novel therapeutic approaches for hypercholesterolemia.
MeSH term(s)	Animals ; Cholesterol/blood ; Disease Models, Animal ; Gene Editing ; Genome ; Humans ; Hypercholesterolemia/genetics ; Hypercholesterolemia/metabolism ; Liver/metabolism ; Mice ; Mice, Transgenic ; Proprotein Convertase 9/genetics
Chemical Substances	Cholesterol (97C5T2UQ7J) ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2019-01-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/s12915-018-0624-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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