title: Prevention and reversal of lipotoxicity-induced hepatic insulin resistance and steatohepatitis in mice by an antioxidant carotenoid, β-cryptoxanthin.
abstract: Excessive hepatic lipid accumulation promotes macrophages/Kupffer cells activation, resulting in exacerbation of insulin resistance and progression of nonalcoholic steatohepatitis (NASH). However, few promising treatment modalities target lipotoxicity-mediated hepatic activation/polarization of macrophages for NASH. Recent epidemiological surveys showed that serum β-cryptoxanthin, an antioxidant carotenoid, was inversely associated with the risks of insulin resistance and liver dysfunction. In the present study, we first showed that β-cryptoxanthin administration ameliorated hepatic steatosis in high-fat diet-induced obese mice. Next, we investigated the preventative and therapeutic effects of β-cryptoxanthin using a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat (CL) diet. After 12 weeks of CL diet feeding, β-cryptoxanthin administration attenuated insulin resistance and excessive hepatic lipid accumulation and peroxidation, with increases in M1-type macrophages/Kupffer cells and activated stellate cells, and fibrosis in CL diet-induced NASH. Comprehensive gene expression analysis showed that β-cryptoxanthin down-regulated macrophage activation signal-related genes significantly without affecting most lipid metabolism-related genes in the liver. Importantly, flow cytometry analysis revealed that, on a CL diet, β-cryptoxanthin caused a predominance of M2 over M1 macrophage populations, in addition to reducing total hepatic macrophage and T-cell contents. In parallel, β-cryptoxanthin decreased lipopolysaccharide-induced M1 marker mRNA expression in peritoneal macrophages, whereas it augmented IL-4-induced M2 marker mRNA expression, in a dose-dependent manner. Moreover, β-cryptoxanthin reversed steatosis, inflammation, and fibrosis progression in preexisting NASH in mice. In conclusion, β-cryptoxanthin prevents and reverses insulin resistance and steatohepatitis, at least in part, through an M2-dominant shift in macrophages/Kupffer cells in a lipotoxic model of NASH.
authors.affiliation: Department of Cell Metabolism and Nutrition (Y.N., M.N., L.Z., N.N., T.O.), Brain/Liver Interface Medicine Research Center, Kanazawa University, and Department of Disease Control and Homeostasis (Y.N., S.K., T.O.), Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan; National Food Research Institute (M.K.), National Agriculture and Food Research Organization, Tsukuba, Ibaraki 305-8642, Japan; Citrus Research Division (M.S.), National Institute of Fruit Tree Science, National Agriculture and Food Research Organization, Shizuoka, Shizuoka 424-0292, Japan; and Grape and Persimmon Research Division (K.O.), National Institute of Fruit Tree Science, National Agriculture and Food Research Organization, Higashi-hiroshima, Hiroshima 739-2494, Japan.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Ni
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nagashimada
authors.forename: Lili
authors.initials: L
authors.lastname: Zhan
authors.forename: Naoto
authors.initials: N
authors.lastname: Nagata
authors.forename: Masuko
authors.initials: M
authors.lastname: Kobori
authors.forename: Minoru
authors.initials: M
authors.lastname: Sugiura
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ogawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D065366:Cryptoxanthins / Q000494:pharmacology*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism; D055166:Hepatic Stellate Cells; D006706:Homeostasis; D007333:Insulin Resistance; D007728:Kupffer Cells; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009765:Obesity
chemical_list: D000975:Antioxidants; D065366:Cryptoxanthins; D004041:Dietary Fats; D005947:Glucose