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: Yinhua Ni, Mayumi Nagashimada, Lili Zhan, Naoto Nagata, Masuko Kobori, Minoru Sugiura, Kazunori Ogawa, Shuichi Kaneko, Tsuguhito Ota
• Journal: Endocrinology (Endocrinology) Vol. 156 Issue 3 Pg. 987-99 (Mar 2015) ISSN: 1945-7170 [Electronic] United States
• PMID: 25562616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Cryptoxanthins
• Dietary Fats
• Glucose

Topics

• Animals
• Antioxidants (pharmacology)
• Cryptoxanthins (pharmacology)
• Dietary Fats (administration & dosage, adverse effects)
• Glucose (metabolism)
• Hepatic Stellate Cells
• Homeostasis
• Insulin Resistance
• Kupffer Cells
• Liver (drug effects, metabolism)
• Liver Cirrhosis
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (chemically induced, metabolism, pathology)
• Obesity