Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)–specific LPL‐knockout (LplHSC‐KO) mice, LPL‐floxed (Lplfl/fl) mice, or double‐mutant toll‐like receptor 4–deficient (Tlr4−/−) LplHSC‐KO mice were fed a high‐fat/high‐cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high‐fat/high‐cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity‐related factors, such as free fatty acid, leptin, and interleukin‐6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC‐KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL‐mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL‐mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.
The serum soluble interleukin 2 receptor (sIL2R) level is elevated in patients with most types of lymphoid neoplasms, and is also elevated in patients with solid tumors or reactive conditions, such as severe inflammation. To evaluate the diagnostic significance of sIL2R levels for the screening and differential diagnosis of lymphomas, data from 248 consecutive adult patients with suspected lymphoma were retrospectively analyzed in order to determine its diagnostic characteristics and the clinical parameters that affect diagnosis. In 133 patients with aggressive or indolent lymphomas or related neoplasms, the sIL2R level was higher (median: 920 U/ml, standard deviation: 7,312 U/ml) compared with that of 115 patients with other diagnoses (median: 520 U/ml, standard deviation: 727 U/ml), including solid tumors, infection, inflammation, and others. When the cutoff value of sIL2R was 1,104 U/ml, the specificity was 80%, at which point lymphoma was suspected. When the threshold levels were increased from 1,500 to 2,000 U/ml, the specificity increased from 87 to 93%, with the positive likelihood ratio increasing from 2.99 to 4.97, strongly suggesting the diagnosis of lymphoma. The receiver operating characteristic curve for prediction of lymphoma by sIL2R revealed that the area under the curve was 0.695. The curve was nearest to the left corner of the plot when the threshold was 1,946 U/ml; at this point, the sensitivity, specificity and positive likelihood ratio were 35%, 93% and 5.06, respectively. Multivariate analysis demonstrated that an age >46 years and lactate dehydrogenase level >173 U/l appeared to increase the risk of malignant lymphoma diagnosis. Although sIL2R appears to be a less specific marker for the screening of lymphomas, its detection at higher levels strongly suggests the diagnosis of lymphomas. Therefore, sIL2R may be more useful compared with any other parameter for lymphoma diagnosis, provided other false-positive conditions are taken into consideration.
Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment.
Aim Chitinase 3‐like 1 (CHI3L1), an 18‐glycosyl hydrolase‐related molecule, is a member of the enzymatically inactive chitinase‐like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. Methods Chitinase 3‐like 1‐deficient (Chi3l1−/−) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline‐deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. Results In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1−/− mice compared to that in wild‐type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1−/− mice compared to that in wild‐type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1−/− mice. Chitinase 3‐like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. Conclusions Chitinase 3‐like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.
Background and AimDietary emulsifiers are widely used in processed foods and officially approved as safe for intake. However, recent studies have demonstrated that some emulsifiers alter the colonic microbiota, leading to colonic low‐grade inflammation, in mice. The effect of dietary emulsifiers on small‐intestinal microbiota, which is important for gut immunity, has not been studied. We aimed to investigate the effect of a representative dietary emulsifier, polysorbate‐80 (P80), on the small‐intestinal microbiota in normal mice.MethodsSome mice were pretreated with P80 for 8 weeks with or without indomethacin administration on the last 2 days, and intestinal damage was evaluated histologically. The ileal and colonic microbiota composition was assessed using 16S rRNA polymerase chain reaction.ResultsPolysorbate‐80 increased the Gammaproteobacteria abundance and decreased the α‐diversity in the small intestine. No decrease in α‐diversity was observed in the colon. P80 pretreatment exacerbated the indomethacin‐induced small‐intestinal lesions and significantly increased the interleukin‐1β expression. Culture of ileal content on deoxycholate hydrogen sulfide lactose agar showed that P80 significantly increased the colonies of the sulfide‐producing bacteria Proteus spp. (genetically identified as Proteus mirabilis). Antibiotic pretreatment abolished the P80‐induced aggravation of indomethacin‐induced ileitis. Motility assay in semisolid agar showed that adding 0.02% P80 to the agar significantly increased the diameter of P. mirabilis colonies but not that of Escherichia coli colonies.ConclusionsPolysorbate‐80 enhances the vulnerability of the small intestine to indomethacin‐induced injury by inducing ileal dysbiosis. Direct enhancement of the motility of specific flagellated microbiota by P80 might be related to dysbiosis and intestinal injury.
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