Objective To investigate the effects of liver-specific leucine carboxyl methyltransferase 1 (LCMT1) gene knockout on glycolipid metabolism, learning and memory in mice and the possible mechanism.
Methods Eight-week-old male wild-type (WT) mice and mice with liver-specific LCMT1 gene knockout (L-LCMT1KO) were selected and fed with a standard diet until they reached 16 weeks of age, with 10 mice in each group. The diet and weight changes of the mice were recorded. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to compare the expression levels of the LCMT1 gene and protein in the liver of the two groups of mice. The liver tissues from the mice were collected for hematoxylin-eosin (HE) staining to observe the histopathological changes in the liver. At 16 weeks of age, the motor ability and spatial learning and memory abilities of the two groups of mice were assessed using the fatigue rotating rod test and the Morris water maze test, respectively. Fasting blood glucose levels were detected, and a glucose tolerance test was performed to assess glucose metabolism. The subcutaneous and visceral fat of the mice were measured, and the fat weights between the two groups were compared. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) were measured using an automatic biochemical analyzer, and the lipid metabolism between the two groups of mice was compared. The expression of PPAR- α, SREBP-1c, Abca1, and LDLR genes in the liver was quantified using RT-qPCR.
Results There was no significant difference in water intake, food intake, energy intake, and body weight between the L-LCMT1KO mice and the WT mice (P > 0.05). The mRNA and protein levels of LCMT1 in the liver of L-LCMT1KO mice were significantly decreased (P < 0.05). HE staining of the liver tissue and serum liver function tests showed that, compared with WT mice, the liver-specific LCMT1 knockout had no effect on liver tissue morphology, serum AST and ALT levels (P > 0.05), and did not impair liver function. Behavioral tests indicated that, compared with WT mice, the liver-specific LCMT1 knockout did not result in motor and balance disorders (P > 0.05) and could enhance their learning and memory abilities (P < 0.05). The results of glucose metabolism tests showed that the L-LCMT1KO mice maintained normal blood glucose levels and glucose tolerance (P > 0.05). The lipid metabolism results indicated that, compared with WT mice, L-LCMT1KO mice exhibited no changes in subcutaneous and visceral fat content, TG level, and LDL-c level (P > 0.05). However, the TC level and HDL-c level were increased (P < 0.05), the TG/HDL-c ratio was decreased (P < 0.05), and the expression of the lipogenic factor SREBP-1c was also decreased (P < 0.05).
Conclusion Liver-specific LCMT1 gene knockout has no significant effect on blood glucose regulation and fat content in mice, but it can enhance their learning and memory abilities. This knockout may regulate cholesterol metabolism pathway by up-regulating HDL-c level and down-regulating liver SREBP-1c expression, thereby affecting learning and memory abilities.
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