Analysis Tools
growth/size/body
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• 8-week-old male mice fed a high-fat diet (HFD) or a high fat-high-cholesterol diet (HFHCD) for 8 weeks show a significant increase in body weight relative to diet-matched wild-type controls
• however, males fed a normal chow diet (NCD) show no significant increase in body weight relative to NCD-fed wild-type controls
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• HFD- and HFHCD-fed male mice exhibit mild hepatomegaly
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• HFD- and HFHCD-fed male mice show a significant increase in liver weight (LW) and liver weight-to-body weight (LW/BW) ratio
• i.v. injection of pLenti-GIII-CMV-Acot12-HA (HA-Acot12) restores liver LW/BW ratio in HFHCD-fed mice
• however, NCD-fed males show normal LW and LW/BW ratio relative to NCD-fed wild-type controls
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liver/biliary system
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• livers of HFD-fed mice show significantly increased immunostaining of PPARA (peroxisome proliferator activated receptor alpha), indicating PPARA overactivation
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• HFD- and HFHCD-fed male mice exhibit mild hepatomegaly
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• HFD- and HFHCD-fed male mice show a significant increase in liver weight (LW) and liver weight-to-body weight (LW/BW) ratio
• i.v. injection of pLenti-GIII-CMV-Acot12-HA (HA-Acot12) restores liver LW/BW ratio in HFHCD-fed mice
• however, NCD-fed males show normal LW and LW/BW ratio relative to NCD-fed wild-type controls
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic total cholesterol (TC) levels
• i.v. injection of HA-Acot12 significantly reduces hepatic TC accumulation in HFHCD-fed mice
• i.p. injection of simvastatin inhibits hepatic TC accumulation in HFHCD-fed mice
• isolated primary hepatocytes show accumulation of cellular cholesterol, as assessed by filipin staining
• treatment of primary hepatocytes with fenofibrate (a known Ppara agonist) fails to reduce cellular TC levels, unlike in wild-type hepatocytes
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic FFA levels
• acetate-treated primary hepatocytes show significantly increased cellular levels of FFAs
• treatment of primary hepatocytes with fenofibrate (a known Ppara agonist) fails to reduce cellular FFA levels, unlike in wild-type hepatocytes
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic triglyceride (TG) levels
• i.v. injection of HA-Acot12 significantly reduces hepatic TG accumulation in HFHCD-fed mice
• i.p. injection of simvastatin inhibits hepatic TG accumulation in HFHCD-fed mice
• acetate-treated primary hepatocytes show significantly increased cellular TG levels
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• isolated primary hepatocytes show increased accumulation of cellular cholesterol, as assessed by filipin staining
• treatment of primary hepatocytes with BODIPY-cholesterol induces cholesterol accumulation; however, the colocalization of BODIPY-cholesterol and lysosomes is lost, unlike in wild-type hepatocytes
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• male mice exhibit severe fat accumulation in the liver under NCD, HFD or HFHCD challenges, as determined by H&E, Oil Red O (ORO), and filipin staining
• i.v. injection of HA-Acot12 significantly reduces the accumulation of lipid droplets (LDs) and alleviates nonalcoholic fatty liver disease (NAFLD) in HFHCD-fed mice
• i.p. injection of the cholesterol-lowering drug simvastatin (an HMG-CoA reductase inhibitor) alleviates hepatic fat accumulation in HFHCD-fed mice
• treatment of HFHCD-fed mice with fenofibrate (a known Ppara agonist) for 6 weeks fails to reduce the accumulation of hepatic LDs and cholesterol, unlike in similarly treated wild-type controls
• in HFD-fed mice, accumulation of hepatic fat and increased levels of hepatic TG and TC are observed after 4 weeks of HFD feeding and appear to be unaffected by an increase in adipose tissue
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homeostasis/metabolism
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic acetyl-CoA levels
• i.v. injection of HA-Acot12 significantly reduces hepatic acetyl-CoA and malonyl CoA levels in HFHCD-fed mice
• acetate-treated primary hepatocytes show significantly increased cellular levels of acetyl-CoA
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• male mice fed a NCD for 8 weeks show impaired glucose tolerance relative to NCD-fed wild-type controls
• severity of impaired glucose tolerance is significantly greater when mice are fed an HFD or a HFHCD for 8 weeks
• i.v. injection of HA-Acot12 rescues the impaired glucose tolerance in HFHCD-fed mice
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• male mice fed a NCD for 8 weeks show insulin resistance relative to NCD-fed wild-type controls
• severity of insulin resistance is significantly greater when mice are fed an HFD or a HFHCD for 8 weeks
• i.v. injection of HA-Acot12 rescues the insulin resistance in HFHCD-fed mice
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic total cholesterol (TC) levels
• i.v. injection of HA-Acot12 significantly reduces hepatic TC accumulation in HFHCD-fed mice
• i.p. injection of simvastatin inhibits hepatic TC accumulation in HFHCD-fed mice
• isolated primary hepatocytes show accumulation of cellular cholesterol, as assessed by filipin staining
• treatment of primary hepatocytes with fenofibrate (a known Ppara agonist) fails to reduce cellular TC levels, unlike in wild-type hepatocytes
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic FFA levels
• acetate-treated primary hepatocytes show significantly increased cellular levels of FFAs
• treatment of primary hepatocytes with fenofibrate (a known Ppara agonist) fails to reduce cellular FFA levels, unlike in wild-type hepatocytes
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• NCD-, HFD-, and HFHCD-fed male mice show a significant increase in hepatic triglyceride (TG) levels
• i.v. injection of HA-Acot12 significantly reduces hepatic TG accumulation in HFHCD-fed mice
• i.p. injection of simvastatin inhibits hepatic TG accumulation in HFHCD-fed mice
• acetate-treated primary hepatocytes show significantly increased cellular TG levels
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• HFD-fed mice show markedly increased mRNA levels of genes encoding lipogenic and cholesterol biosynthesis enzymes in the liver; genes involved in de novo lipogenesis (DNL) and mevalonate pathways are significantly upregulated relative to HFD-fed wild-type livers
• i.v. injection of HA-Acot12 significantly reduces the mRNA levels of genes involved in lipogenesis and cholesterol biosynthesis in HFHCD-fed mice
• acetate-treated primary hepatocytes show significantly increased expression levels of Ppara and lipogenic genes
• treatment of primary hepatocytes with fenofibrate (a known Ppara agonist) induces Ppara expression and cellular acetyl CoA levels but fails to lower cellular TC or FFA levels and instead leads to a greater increase in cellular lipids and cholesterol with further upregulation of DNL and cholesterol synthesis genes
• similar to cultured cells, fenofibrate-treated HFHCD-fed mice show a marked increase in the accumulation of hepatic lipid droplets and cholesterol along with upregulation of DNL and cholesterol synthesis genes
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cellular
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• treatment of primary hepatocytes with BODIPY-cholesterol induces cholesterol accumulation; however, the colocalization of BODIPY-cholesterol and lysosomes is lost, unlike in wild-type hepatocytes where most lysosomes contain cholesterol
• a lack of cholesterol in lysosomes and the finding that ACOT12 interacts with VPS33A (vacuolar protein sorting-associated protein 33A) suggests altered vesicle-mediated cholesterol trafficking in primary hepatocytes
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