Martine C Morrison1, Wen Liang2, Petra Mulder2, Lars Verschuren2, Elsbet Pieterman2, Karin Toet2, Peter Heeringa3, Peter Y Wielinga2, Teake Kooistra2, Robert Kleemann2. 1. Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), 9713 GZ Groningen, The Netherlands; Top Institute Food and Nutrition, Nieuwe Kanaal 9A, 6709 PA Wageningen, The Netherlands. Electronic address: martine.morrison@tno.nl. 2. Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands. 3. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (EA11), 9713 GZ Groningen, The Netherlands.
Abstract
BACKGROUND & AIMS: Anthocyanins may have beneficial effects on lipid metabolism and inflammation and are demonstrated to have hepatoprotective properties in models of restraint-stress- and chemically-induced liver damage. However, their potential to protect against non-alcoholic steatohepatitis (NASH) under conditions relevant for human pathogenesis remains unclear. Therefore, we studied the effects of the standardised anthocyanin-rich extract Mirtoselect on diet-induced NASH in a translational model of disease. METHODS: ApoE(∗)3Leiden mice were fed a Western-type cholesterol-containing diet without (HC) or with 0.1% (w/w) Mirtoselect (HCM) for 20weeks to study the effects on diet-induced NASH. RESULTS: Mirtoselect attenuated HC-induced hepatic steatosis, as observed by decreased macro- and microvesicular hepatocellular lipid accumulation and reduced hepatic cholesteryl ester content. This anti-steatotic effect was accompanied by local anti-inflammatory effects in liver, as demonstrated by reduced inflammatory cell clusters and reduced neutrophil infiltration in HCM. On a molecular level, HC diet significantly induced hepatic expression of pro-inflammatory genes Tnf, Emr1, Ccl2, Mpo, Cxcl1, and Cxcl2 while this induction was less pronounced or significantly decreased in HCM. A similar quenching effect was observed for HC-induced pro-fibrotic genes, Acta2 and Col1a1 and this anti-fibrotic effect of Mirtoselect was confirmed histologically. Many of the pro-inflammatory and pro-fibrotic parameters positively correlated with intrahepatic free cholesterol levels. Mirtoselect significantly reduced accumulation and crystallisation of intrahepatic free cholesterol, providing a possible mechanism for the observed hepatoprotective effects. CONCLUSIONS: Mirtoselect attenuates development of NASH, reducing hepatic lipid accumulation, inflammation and fibrosis, possibly mediated by local anti-inflammatory effects associated with reduced accumulation and crystallisation of intrahepatic free cholesterol.
BACKGROUND & AIMS:Anthocyanins may have beneficial effects on lipid metabolism and inflammation and are demonstrated to have hepatoprotective properties in models of restraint-stress- and chemically-induced liver damage. However, their potential to protect against non-alcoholic steatohepatitis (NASH) under conditions relevant for human pathogenesis remains unclear. Therefore, we studied the effects of the standardised anthocyanin-rich extract Mirtoselect on diet-induced NASH in a translational model of disease. METHODS:ApoE(∗)3Leiden mice were fed a Western-type cholesterol-containing diet without (HC) or with 0.1% (w/w) Mirtoselect (HCM) for 20weeks to study the effects on diet-induced NASH. RESULTS:Mirtoselect attenuated HC-induced hepatic steatosis, as observed by decreased macro- and microvesicular hepatocellular lipid accumulation and reduced hepatic cholesteryl ester content. This anti-steatotic effect was accompanied by local anti-inflammatory effects in liver, as demonstrated by reduced inflammatory cell clusters and reduced neutrophil infiltration in HCM. On a molecular level, HC diet significantly induced hepatic expression of pro-inflammatory genes Tnf, Emr1, Ccl2, Mpo, Cxcl1, and Cxcl2 while this induction was less pronounced or significantly decreased in HCM. A similar quenching effect was observed for HC-induced pro-fibrotic genes, Acta2 and Col1a1 and this anti-fibrotic effect of Mirtoselect was confirmed histologically. Many of the pro-inflammatory and pro-fibrotic parameters positively correlated with intrahepatic free cholesterol levels. Mirtoselect significantly reduced accumulation and crystallisation of intrahepatic free cholesterol, providing a possible mechanism for the observed hepatoprotective effects. CONCLUSIONS:Mirtoselect attenuates development of NASH, reducing hepatic lipid accumulation, inflammation and fibrosis, possibly mediated by local anti-inflammatory effects associated with reduced accumulation and crystallisation of intrahepatic free cholesterol.
Authors: Michael Zimmer; Pradeep Bista; Ericka L Benson; Diana Y Lee; Feng Liu; Dominic Picarella; Rick B Vega; Chi B Vu; Maisy Yeager; Min Ding; Guosheng Liang; Jay D Horton; Robert Kleemann; Teake Kooistra; Martine C Morrison; Peter Y Wielinga; Jill C Milne; Michael R Jirousek; Andrew J Nichols Journal: Hepatol Commun Date: 2017-05-12
Authors: Martine C Morrison; Robert Kleemann; Arianne van Koppen; Roeland Hanemaaijer; Lars Verschuren Journal: Front Physiol Date: 2018-02-23 Impact factor: 4.566
Authors: Martine C Morrison; Petra Mulder; P Mark Stavro; Manuel Suárez; Anna Arola-Arnal; Wim van Duyvenvoorde; Teake Kooistra; Peter Y Wielinga; Robert Kleemann Journal: PLoS One Date: 2015-09-25 Impact factor: 3.240
Authors: Roel A van der Heijden; Martine C Morrison; Fareeba Sheedfar; Petra Mulder; Marijke Schreurs; Pascal P H Hommelberg; Marten H Hofker; Casper Schalkwijk; Robert Kleemann; Uwe J F Tietge; Debby P Y Koonen; Peter Heeringa Journal: Mediators Inflamm Date: 2016-06-06 Impact factor: 4.711
Authors: M C Morrison; P Mulder; K Salic; J Verheij; W Liang; W van Duyvenvoorde; A Menke; T Kooistra; R Kleemann; P Y Wielinga Journal: Int J Obes (Lond) Date: 2016-05-28 Impact factor: 5.095
Authors: Marieke H Schoemaker; Robert Kleemann; Martine C Morrison; Joanne Verheij; Kanita Salic; Eric A F van Tol; Teake Kooistra; Peter Y Wielinga Journal: PLoS One Date: 2017-07-05 Impact factor: 3.240