Abstract
Sterol regulatory element-binding protein-1c (SREBP-1c) increases lipogenesis at the transcriptional level, and its expression is upregulated by liver X receptor α (LXRα). The LXRα/SREBP-1c signaling may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We previously reported that a cholesterol metabolite, 5-cholesten-3β,25-diol 3-sulfate (25HC3S), inhibits the LXRα signaling and reduces lipogenesis by decreasing SREBP-1c expression in primary hepatocytes. The present study aims to investigate the effects of 25HC3S on lipid homeostasis in diet-induced NAFLD mouse models. NAFLD was induced by feeding a high-fat diet (HFD) in C57BL/6J mice. The effects of 25HC3S on lipid homeostasis, inflammatory responses, and insulin sensitivity were evaluated after acute treatments or long-term treatments. Acute treatments with 25HC3S decreased serum lipid levels, and long-term treatments decreased hepatic lipid accumulation in the NAFLD mice. Gene expression analysis showed that 25HC3S significantly suppressed the SREBP-1c signaling pathway that was associated with the suppression of the key enzymes involved in lipogenesis: fatty acid synthase, acetyl-CoA carboxylase 1, and glycerol-3-phosphate acyltransferase. In addition, 25HC3S significantly reduced HFD-induced hepatic inflammation as evidenced by decreasing tumor necrosis factor and interleukin 1 α/β mRNA levels. A glucose tolerance test and insulin tolerance test showed that 25HC3S administration improved HFD-induced insulin resistance. The present results indicate that 25HC3S as a potent endogenous regulator decreases lipogenesis, and oxysterol sulfation can be a key protective regulatory pathway against lipid accumulation and lipid-induced inflammation in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetyl-CoA Carboxylase / genetics
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Acetyl-CoA Carboxylase / metabolism
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Acetyltransferases / genetics
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Acetyltransferases / metabolism
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Animals
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Cholesterol Esters / pharmacology*
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Diet, High-Fat / adverse effects*
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Fatty Acids / metabolism
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Fatty Liver / blood
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Fatty Liver / chemically induced
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Fatty Liver / drug therapy*
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Fatty Liver / genetics
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Fatty Liver / metabolism
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Female
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Gene Expression / genetics
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Glucose Tolerance Test / methods
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Glycerol-3-Phosphate O-Acyltransferase / genetics
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Glycerol-3-Phosphate O-Acyltransferase / metabolism
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Hydroxycholesterols / pharmacology*
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Inflammation / metabolism
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Insulin / genetics
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Insulin / metabolism
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Insulin Resistance / genetics
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Interleukin-1alpha / genetics
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Interleukin-1alpha / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Lipid Metabolism / drug effects*
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Lipid Metabolism / genetics
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Lipids / blood*
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Liver / drug effects
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Liver / metabolism*
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Mice
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Mice, Inbred C57BL
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Non-alcoholic Fatty Liver Disease
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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25-hydroxycholesterol 3-sulfate
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Cholesterol Esters
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Fatty Acids
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Hydroxycholesterols
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Insulin
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Interleukin-1alpha
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Interleukin-1beta
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Lipids
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Srebf1 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Tumor Necrosis Factor-alpha
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fas Receptor
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Acetyltransferases
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aminoglycoside N1-acetyltransferase
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Glycerol-3-Phosphate O-Acyltransferase
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glycerol-3-phosphate acyltransferase 2, mouse
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Acetyl-CoA Carboxylase