Cytarabine induces cachexia with lipid malabsorption via zippering the junctions of lacteal in murine small intestine |
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Affiliation: | 1. Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea;2. Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea;3. Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea;4. Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea;5. Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Republic of Korea |
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Abstract: | Chemotherapy-induced cachexia causes severe metabolic abnormalities independently of cancer and reduces the therapeutic efficacy of chemotherapy. The underlying mechanism of chemotherapy-induced cachexia remains unclear. Here we investigated the cytarabine (CYT)-induced alteration in energy balance and its underlying mechanisms in mice. We compared energy balance-associated parameters among the three groups of mice: CON, CYT, and PF (pair-fed mice with the CYT group) that were intravenously administered vehicle or CYT. Weight gain, fat mass, skeletal muscle mass, grip strength, and nocturnal energy expenditure were significantly lowered in the CYT group than in the CON and PF groups. The CYT group demonstrated less energy intake than the CON group and higher respiratory quotient than the PF group, indicating that CYT induced cachexia independently from the anorexia-induced weight loss. Serum triglyceride was significantly lower in the CYT group than in the CON group, whereas the intestinal mucosal triglyceride levels and the lipid content within the small intestine enterocyte were higher after lipid loading in the CYT group than in the CON and PF groups, suggesting that CYT inhibited lipid uptake in the intestine. This was not associated with obvious intestinal damage. The CYT group showed increased zipper-like junctions of lymphatic endothelial vessel in duodenal villi compared to that in the CON and CYT groups, suggesting their imperative role in the CYT-induced inhibition of lipid uptake. CYT worsens cachexia independently of anorexia by inhibiting the intestinal lipid uptake, via the increased zipper-like junctions of lymphatic endothelial vessel. |
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Keywords: | cytarabine triglycerides metabolic dysfunction cachexia malabsorption small intestine lymphatic endothelial cell lacteal ALT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" alanine aminotransferase AST" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" aspartate aminotransferase AUC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" area under the curve BAT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" brown adipose tissue CM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" chylomicron CON" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" control CYT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" cytarabine EE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0125" }," $$" :[{" #name" :" text" ," _" :" energy expenditure eWAT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" epididymal white adipose tissue GI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0145" }," $$" :[{" #name" :" text" ," _" :" gastrointestinal LEC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0155" }," $$" :[{" #name" :" text" ," _" :" lymphatic endothelial cell oFTT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0165" }," $$" :[{" #name" :" text" ," _" :" oral fat tolerance test ORO" },{" #name" :" keyword" ," $" :{" id" :" kwrd0175" }," $$" :[{" #name" :" text" ," _" :" oil red O PF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0185" }," $$" :[{" #name" :" text" ," _" :" pair-fed PFA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0195" }," $$" :[{" #name" :" text" ," _" :" paraformaldehyde RQ" },{" #name" :" keyword" ," $" :{" id" :" kwrd0205" }," $$" :[{" #name" :" text" ," _" :" respiratory quotient TEM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0215" }," $$" :[{" #name" :" text" ," _" :" transmission electron microscopy TG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0225" }," $$" :[{" #name" :" text" ," _" :" triglyceride TGN" },{" #name" :" keyword" ," $" :{" id" :" kwrd0235" }," $$" :[{" #name" :" text" ," _" :" trans-Golgi network |
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