Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease |
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Affiliation: | 1. Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA;2. Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan;3. Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA;4. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA;5. Department of Pharmaceutical Sciences, Kindai University, Osaka, Japan;6. Division of Research and Development, Genmaikoso Co. Ltd., Sapporo, Hokkaido, Japan;7. Junshin Clinic Bile Acid Institute, Tokyo, Japan;8. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA |
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Abstract: | CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1−/− mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1−/− mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1−/− mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1−/− mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease. |
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Keywords: | Cholesterol metabolism Oxysterols Bile acid and salts Inflammation Insulin Resistance Fatty liver Hepatotoxicity 26HC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" (" },{" #name" :" italic" ," _" :" 25R" },{" #name" :" __text__" ," _" :" )26-hydroxycholestetol (also known as 27-hydroxycholesterol) 26HC3S" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" (" },{" #name" :" italic" ," _" :" 25R" },{" #name" :" __text__" ," _" :" )26-hydroxycholesterol-3β-sulfate 3βHCA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" 3β-hydroxy-5-cholesten-(" },{" #name" :" italic" ," _" :" 25R" },{" #name" :" __text__" ," _" :" )26-oic acid AST" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" aspartate aminotransferase ALT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" alanine transaminase BA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" bile acid CYP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" (Cyp denotes murine), cytochrome P450 CA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" cholic acid diHCA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" dihydroxycholestenoic acid DCA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" deoxycholic acid DEG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" differentially expressed gene DM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" diabetes mellitus EC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" epoxycholesterol GO" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" Gene Ontology HCD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" high-cholesterol diet HFLCD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0200" }," $$" :[{" #name" :" text" ," _" :" high-fat low-cholesterol diet HOMA-IR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0210" }," $$" :[{" #name" :" text" ," _" :" Homeostatic Model Assessment of Insulin Resistance IR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0220" }," $$" :[{" #name" :" text" ," _" :" insulin resistance IS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0230" }," $$" :[{" #name" :" text" ," _" :" internal standard KC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0240" }," $$" :[{" #name" :" text" ," _" :" ketocholesterol MCA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0250" }," $$" :[{" #name" :" text" ," _" :" muricholic acid NAFL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0260" }," $$" :[{" #name" :" text" ," _" :" nonalcoholic fatty liver NASH" },{" #name" :" keyword" ," $" :{" id" :" kwrd0270" }," $$" :[{" #name" :" text" ," _" :" nonalcoholic steatohepatitis NAFLD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0280" }," $$" :[{" #name" :" text" ," _" :" nonalcoholic fatty liver disease ND" },{" #name" :" keyword" ," $" :{" id" :" kwrd0290" }," $$" :[{" #name" :" text" ," _" :" normal diet WD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0300" }," $$" :[{" #name" :" text" ," _" :" Western diet RNA-seq" },{" #name" :" keyword" ," $" :{" id" :" kwrd0310" }," $$" :[{" #name" :" text" ," _" :" RNA sequencing SPG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0320" }," $$" :[{" #name" :" text" ," _" :" spastic paraplegia TBA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0330" }," $$" :[{" #name" :" text" ," _" :" total bile acid TC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0340" }," $$" :[{" #name" :" text" ," _" :" total cholesterol TG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0350" }," $$" :[{" #name" :" text" ," _" :" triglyceride |
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