Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice

Abstract

Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.

Oxysterols in stored powders as potential health hazards

“…The sum of C7 cholesterol oxides (7α-HC, 7β-HC, 7-KC) in milk powders after production was 0.4 µg g −1 powder, which is consistent with the results of this study (0.3 µg g −1 powder). As recently reviewed by Chang et al 36 the addition of small quantities of dietary 7-KC contributed to accelerated hepatic steatosis and inflammation in obese mice models.…”

Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy

“…In the current study, we developed a high fat/high cholesterol/high sucrose/bile acid diet 29 . In this model, steatohepatitis was characterized by more accumulation of free cholesterol and cholesterol crystals than other steatosis models, such as ob/ob mice fed a high-fat diet 30 , thus leading to activation of the inflammasome pathway, including NLRP3 and IL-1β (Fig. 7 ).…”

“…RT–qPCR and western blotting were performed as described previously 30 . Briefly, total RNA was isolated from liver tissues using the RNeasy® Mini Kit (QIAGEN, Hilden, Germany).…”

“…RNA sequence analysis was conducted as described previously 30 . Briefly, sequencing was performed on an Illumina HiSeq 2500 platform in 75-base single-end mode.…”

Dietary 7-Ketocholesterol Exacerbates Myocardial Ischemia–Reperfusion Injury in Mice through Monocyte/Macrophage-Mediated Inflammation

“…25 Therefore, our ndings could be translated into practice through clinical trials. Furthermore, because it has been reported that 7-KC is related to other cardiometabolic diseases, such as nonalcoholic fatty liver disease 45 and age-related macular degeneration, 46 7-KC could also be a therapeutic target in such diseases. It is noteworthy that the 7-KC level was signi cantly increased in heart tissue, not only in the blood (data not shown), and the related roles should be explored in other heart diseases.…”