Analysis Tools
growth/size/body
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• after 2-3 weeks on a diet enriched in phytol (a precursor of phytanic acid, 0.5% (w/w)), both female and male mice show a ~15% loss in body weight relative to phytol-fed wild-type controls, with no significant change in food intake
• in contrast, mice fed a diet enriched in racemic 2OH-tetradecanoic acid or the longer analogue, 2OH-octadecanoic acid, show no significant weight loss or pathology
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• all phytol-fed mice exhibit hepatomegaly
• however, phytol feeding has no effect on kidney or intestine morphology
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• phytol-fed mice exhibit a significantly higher liver weight/body weight ratio than mice fed a regular chow diet or wild-type mice fed a phytol-enriched diet
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liver/biliary system
| N |
• under standard laboratory conditions, mice are born alive, develop normally, and exhibit normal liver histology
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• after 2-3 weeks on a phytol-enriched diet, all mice exhibit a markedly enlarged and mottled liver, unlike phytol-fed wild-type mice
• both female and male phytol-fed mice show a drastic accumulation of phytanic acid in their livers (~430 pmol/nmol phospholipid)
• phytol-fed mice show a marked induction in hepatic protein expression of CYP4A (a PPAR-alpha target) that is more obvious in the periportal region, consistent with hepatic PPARalpha activation
• however, hepatic levels of cholesteryl esters, cholesterol, and plasmalogen are not significantly altered in mice whether fed a regular chow or a phytol-enriched diet
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• all phytol-fed mice exhibit hepatomegaly
• however, phytol feeding has no effect on kidney or intestine morphology
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• phytol-fed mice exhibit a significantly higher liver weight/body weight ratio than mice fed a regular chow diet or wild-type mice fed a phytol-enriched diet
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• both female and male phytol-fed mice show a significantly lower hepatic glycogen content than phytol-fed wild-type mice
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• phytol-fed female mice show a moderate but significant reduction in liver triglyceride levels relative to females fed a regular chow diet (when normalized to phospholipids)
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• after 2-3 weeks on a phytol-enriched diet, ORO staining shows an irregular distribution of neutral lipids across the liver parenchyma, in the absence of massive neutral lipid accumulation; neutral lipids are more abundant in the periportal area than in the centrilobular region
• livers of phytol-fed mice show both micro-and macrovesicular steatosis with absence of neutral lipids in the centrilobular area, whereas wild-type livers show only isolated microvesicular steatosis
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homeostasis/metabolism
| N |
• phytol-fed mice show no significant differences in feces bile acid content or biliary bile acid composition and amount relative to phytol-fed wild-type mice
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• under normal conditions, hepatocytes of non-phytol-treated mice show a >60% reduction in alpha-oxidation of 3-methylhexadecanoic acid (a phytanic acid analogue)
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• phytol-fed male mice show liver damage with a significantly higher level of liver-derived alkaline phosphatase in serum than males fed a regular chow diet or wild-type males fed a phytol-enriched diet
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• both female and male phytol-fed mice show a significantly lower hepatic glycogen content than phytol-fed wild-type mice
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• both female and male phytol-fed mice show a drastic elevation of phytanic acid in liver (~430 pmol/nmol phospholipid) and serum (~1 mM), with less phytanic acid accumulated in the heart, kidney, spleen, lung, and Harderian gland (10-30 pmol/nmol phospholipid)
• phytol-fed mice also show a modest increase of 2-hydroxyphytanic acid levels (~70 pmol/nmol phospholipid in liver and 70 uM in serum), and to a lesser extent of pristanic acid and the downstream beta-oxidation product 4,8,12-trimethyltridecanoic acid
• in phytol-fed mice, the levels of 2-hydroxyphytanic acid found in liver and serum and of its CoA-ester in liver are lower than those of phytanic acid, suggesting an alternative salvage pathway for phytanic acid breakdown
• however, no accumulation of (very) long chain 2-hydroxy fatty acids (2OH-FA) is detected in the liver or brain even after treatment with a 2OH-FA-enriched diet; moreover, total levels of saturated and unsaturated, as well as odd chain fatty acids, the alpha-oxidation products of 2OH-FA, are not altered in brain
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• phytol-fed female mice show a moderate but significant reduction in liver triglyceride levels relative to females fed a regular chow diet (when normalized to phospholipids)
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• phyto-fed mice show presence of 2,6-dimethylheptanedioic acid (2,6M-diC7) and 2,6-dimethylnonanedioic acid (2,6M-diC9) in the urine, suggesting that the (accumulating) pristanic acid is partially omega-oxidized and further shortened by beta-oxidation
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• fresh liver homogenates from mice fed a regular chow diet show some residual hepatic lyase activity that is ~15% of controls, whereas kidney homogenates show a residual lyase activity that is ~50%-70% of controls with a specific activity similar to that detected in lyase deficient livers
• phytol-fed mice show a marked increase of phytanoyl-CoA levels and to a lesser extent of 2-hydroxyphytanoyl-CoA levels in the liver
• fresh liver homogenates from phytol-fed mice show a significant increase in Ehhadh (enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase, aka MFP1) activity, 2-fold in females and 4-fold in males, relative to phytol-fed wild type mice, consistent with hepatic PPAR-alpha activation
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adipose tissue
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• after 2-3 weeks on a phytol-enriched diet, mice show almost no abdominal white adipose tissue, unlike phytol-fed wild-type mice
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• both female and male mice fed a diet enriched in 2OH-octadecanoic acid show a slightly higher % of fat mass than diet-matched wild-type controls (28.0% vs 21.7% in females and 21.7% vs 15.6% in males)
• however, neither histological abnormalities nor changes in (very) long chain 2-hydroxy fatty acids (2OH-FA) are detectable in lipid extracts
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renal/urinary system
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• phyto-fed mice show presence of 2,6-dimethylheptanedioic acid (2,6M-diC7) and 2,6-dimethylnonanedioic acid (2,6M-diC9) in the urine, suggesting that the (accumulating) pristanic acid is partially omega-oxidized and further shortened by beta-oxidation
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nervous system
| N |
• phytol-fed mice exhibit no evidence of neuroinflammation, no signs of axonal degeneration or demyelination in the corpus callosum or cerebellum, and no Purkinje cell loss in the cerebellum, indicating that the CNS is largely spared
• no accumulation of (very) long chain 2-hydroxy fatty acids (2OH-FA) is detected in the CNS, likely due to the presence in the endoplasmic reticulum of an alternate HACL1-unrelated lyase
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astrocytosis
(
J:255067
)
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• phytol-fed mice show mild astrocytosis, with some GFAP staining observed in the corpus callosum and more positive staining seen in the cerebellum, although with some variability between mice
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cellular
astrocytosis
(
J:255067
)
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• phytol-fed mice show mild astrocytosis, with some GFAP staining observed in the corpus callosum and more positive staining seen in the cerebellum, although with some variability between mice
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• under normal conditions, hepatocytes of non-phytol-treated mice show a >60% reduction in alpha-oxidation of 3-methylhexadecanoic acid (a phytanic acid analogue)
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behavior/neurological
| N |
• phytol-fed mice exhibit a normal footprint pattern (no ataxia) and show normal performance in tail suspension, hanging wire, vertical pole, and rotarod tests
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