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Gene expression profile analysis of type 2 diabetic mouse liver.

Zhang F, Xu X, Zhang Y, Zhou B, He Z, Zhai Q - PLoS ONE (2013)

Bottom Line: Analysis of the key enzyme genes in fatty acid and glucose metabolism showed that some key enzyme genes were significantly increased and none of the detected key enzyme genes were decreased.In addition, FunDo analysis showed that liver cancer and hepatitis were most likely to be associated with diabetes.Taken together, this study provides the digital gene expression profile of diabetic mouse liver, and demonstrates the main diabetes-associated hepatic biological processes, pathways, key enzyme genes in fatty acid and glucose metabolism and potential hepatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Liver plays a key role in glucose metabolism and homeostasis, and impaired hepatic glucose metabolism contributes to the development of type 2 diabetes. However, the precise gene expression profile of diabetic liver and its association with diabetes and related diseases are yet to be further elucidated. In this study, we detected the gene expression profile by high-throughput sequencing in 9-week-old normal and type 2 diabetic db/db mouse liver. Totally 12132 genes were detected, and 2627 genes were significantly changed in diabetic mouse liver. Biological process analysis showed that the upregulated genes in diabetic mouse liver were mainly enriched in metabolic processes. Surprisingly, the downregulated genes in diabetic mouse liver were mainly enriched in immune-related processes, although all the altered genes were still mainly enriched in metabolic processes. Similarly, KEGG pathway analysis showed that metabolic pathways were the major pathways altered in diabetic mouse liver, and downregulated genes were enriched in immune and cancer pathways. Analysis of the key enzyme genes in fatty acid and glucose metabolism showed that some key enzyme genes were significantly increased and none of the detected key enzyme genes were decreased. In addition, FunDo analysis showed that liver cancer and hepatitis were most likely to be associated with diabetes. Taken together, this study provides the digital gene expression profile of diabetic mouse liver, and demonstrates the main diabetes-associated hepatic biological processes, pathways, key enzyme genes in fatty acid and glucose metabolism and potential hepatic diseases.

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The expression of enzymes directly participated in fatty acid β-oxidation, synthesis and storage was increased or not significantly changed in diabetic mouse liver.(A) Schematic of fatty acid metabolism and the expression of enzymes directly participated in fatty acid oxidation, synthesis and storage in diabetic mouse liver. Red color represents the enzyme genes upregulated in diabetic mouse liver with fold change ≥ 1.5 and FDR < 0.001, gray color indicates no significant change, and white color indicates the genes were not detected. (B–C) The mRNA levels of the enzymes directly participated in fatty acid oxidation, synthesis and storage in normal (N) and diabetic (DB) mouse liver. ACS, acetyl-CoA synthesis; CAT, carnitine acyl transferase; CPT, carnitine palmitoyltransferase; ACD, acyl-CoA dehydrogenase; EHHADH, enoyl-CoA-hydratase/3-hydroxyacyl-CoA dehydrogenase; ACAT, acetyl-CoA acetyltransferase; ACL, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ELOVL6, long-chain elongase; SCD1, stearoyl-CoA desaturase 1; GPAT, mitochondrial glycerol 3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase.
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pone-0057766-g003: The expression of enzymes directly participated in fatty acid β-oxidation, synthesis and storage was increased or not significantly changed in diabetic mouse liver.(A) Schematic of fatty acid metabolism and the expression of enzymes directly participated in fatty acid oxidation, synthesis and storage in diabetic mouse liver. Red color represents the enzyme genes upregulated in diabetic mouse liver with fold change ≥ 1.5 and FDR < 0.001, gray color indicates no significant change, and white color indicates the genes were not detected. (B–C) The mRNA levels of the enzymes directly participated in fatty acid oxidation, synthesis and storage in normal (N) and diabetic (DB) mouse liver. ACS, acetyl-CoA synthesis; CAT, carnitine acyl transferase; CPT, carnitine palmitoyltransferase; ACD, acyl-CoA dehydrogenase; EHHADH, enoyl-CoA-hydratase/3-hydroxyacyl-CoA dehydrogenase; ACAT, acetyl-CoA acetyltransferase; ACL, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ELOVL6, long-chain elongase; SCD1, stearoyl-CoA desaturase 1; GPAT, mitochondrial glycerol 3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase.

Mentions: The differentially expressed genes were enriched in lipid metabolic process and fatty acid metabolic process (Figure 2), and it is well known that fatty acid metabolism is impaired in diabetic liver [12], [13]. So we analyzed the transcriptional level of enzyme genes participated in fatty acid metabolism. Schematic of three major fatty acid metabolism subprocesses including fatty acid oxidation, fatty acid synthesis and fatty acid storage were shown in Figure 3A. Surprisingly, none of these detected enzyme genes was downregulated in diabetic mouse liver, and most of the enzyme genes in fatty acid oxidation and fatty acid storage were significantly upregulated (Figure 3A–C). For example, Cpt1a and Cpt2 encoding the rate-limiting enzyme carnitine-palmitoyl transferase in fatty acid oxidation were upregulated to 1.36-fold and 1.66-fold respectively in diabetic mouse liver, and Ehhadh encoding the key enzyme catalyzing two steps in fatty acid oxidation was increased to 3.99-fold (Figure 3B). Moreover, the enzyme genes Elovl6, Scd1, Gpat, Dgat1 and Dgat2, encoding fatty acid storage enzymes long-chain elongase (ELOVL6), stearoyl-CoA desaturase 1 (SCD1), mitochondrial glycerol 3-phosphate acyltransferase (GPAT) and diacylglycerol acyltransferase (DGAT), were upregulated to 3.01-, 1.89-, 2.37-, 6.67- and 1.48-fold respectively (Figure 3C). Whereas the enzyme genes involved in fatty acid synthesis, including Acly and Fasn showed no significant change (Figure 3C). These results suggest that fatty acid oxidation and storage are enhanced in 9-week-old diabetic db/db mouse liver.


Gene expression profile analysis of type 2 diabetic mouse liver.

Zhang F, Xu X, Zhang Y, Zhou B, He Z, Zhai Q - PLoS ONE (2013)

The expression of enzymes directly participated in fatty acid β-oxidation, synthesis and storage was increased or not significantly changed in diabetic mouse liver.(A) Schematic of fatty acid metabolism and the expression of enzymes directly participated in fatty acid oxidation, synthesis and storage in diabetic mouse liver. Red color represents the enzyme genes upregulated in diabetic mouse liver with fold change ≥ 1.5 and FDR < 0.001, gray color indicates no significant change, and white color indicates the genes were not detected. (B–C) The mRNA levels of the enzymes directly participated in fatty acid oxidation, synthesis and storage in normal (N) and diabetic (DB) mouse liver. ACS, acetyl-CoA synthesis; CAT, carnitine acyl transferase; CPT, carnitine palmitoyltransferase; ACD, acyl-CoA dehydrogenase; EHHADH, enoyl-CoA-hydratase/3-hydroxyacyl-CoA dehydrogenase; ACAT, acetyl-CoA acetyltransferase; ACL, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ELOVL6, long-chain elongase; SCD1, stearoyl-CoA desaturase 1; GPAT, mitochondrial glycerol 3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585940&req=5

pone-0057766-g003: The expression of enzymes directly participated in fatty acid β-oxidation, synthesis and storage was increased or not significantly changed in diabetic mouse liver.(A) Schematic of fatty acid metabolism and the expression of enzymes directly participated in fatty acid oxidation, synthesis and storage in diabetic mouse liver. Red color represents the enzyme genes upregulated in diabetic mouse liver with fold change ≥ 1.5 and FDR < 0.001, gray color indicates no significant change, and white color indicates the genes were not detected. (B–C) The mRNA levels of the enzymes directly participated in fatty acid oxidation, synthesis and storage in normal (N) and diabetic (DB) mouse liver. ACS, acetyl-CoA synthesis; CAT, carnitine acyl transferase; CPT, carnitine palmitoyltransferase; ACD, acyl-CoA dehydrogenase; EHHADH, enoyl-CoA-hydratase/3-hydroxyacyl-CoA dehydrogenase; ACAT, acetyl-CoA acetyltransferase; ACL, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ELOVL6, long-chain elongase; SCD1, stearoyl-CoA desaturase 1; GPAT, mitochondrial glycerol 3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase.
Mentions: The differentially expressed genes were enriched in lipid metabolic process and fatty acid metabolic process (Figure 2), and it is well known that fatty acid metabolism is impaired in diabetic liver [12], [13]. So we analyzed the transcriptional level of enzyme genes participated in fatty acid metabolism. Schematic of three major fatty acid metabolism subprocesses including fatty acid oxidation, fatty acid synthesis and fatty acid storage were shown in Figure 3A. Surprisingly, none of these detected enzyme genes was downregulated in diabetic mouse liver, and most of the enzyme genes in fatty acid oxidation and fatty acid storage were significantly upregulated (Figure 3A–C). For example, Cpt1a and Cpt2 encoding the rate-limiting enzyme carnitine-palmitoyl transferase in fatty acid oxidation were upregulated to 1.36-fold and 1.66-fold respectively in diabetic mouse liver, and Ehhadh encoding the key enzyme catalyzing two steps in fatty acid oxidation was increased to 3.99-fold (Figure 3B). Moreover, the enzyme genes Elovl6, Scd1, Gpat, Dgat1 and Dgat2, encoding fatty acid storage enzymes long-chain elongase (ELOVL6), stearoyl-CoA desaturase 1 (SCD1), mitochondrial glycerol 3-phosphate acyltransferase (GPAT) and diacylglycerol acyltransferase (DGAT), were upregulated to 3.01-, 1.89-, 2.37-, 6.67- and 1.48-fold respectively (Figure 3C). Whereas the enzyme genes involved in fatty acid synthesis, including Acly and Fasn showed no significant change (Figure 3C). These results suggest that fatty acid oxidation and storage are enhanced in 9-week-old diabetic db/db mouse liver.

Bottom Line: Analysis of the key enzyme genes in fatty acid and glucose metabolism showed that some key enzyme genes were significantly increased and none of the detected key enzyme genes were decreased.In addition, FunDo analysis showed that liver cancer and hepatitis were most likely to be associated with diabetes.Taken together, this study provides the digital gene expression profile of diabetic mouse liver, and demonstrates the main diabetes-associated hepatic biological processes, pathways, key enzyme genes in fatty acid and glucose metabolism and potential hepatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Liver plays a key role in glucose metabolism and homeostasis, and impaired hepatic glucose metabolism contributes to the development of type 2 diabetes. However, the precise gene expression profile of diabetic liver and its association with diabetes and related diseases are yet to be further elucidated. In this study, we detected the gene expression profile by high-throughput sequencing in 9-week-old normal and type 2 diabetic db/db mouse liver. Totally 12132 genes were detected, and 2627 genes were significantly changed in diabetic mouse liver. Biological process analysis showed that the upregulated genes in diabetic mouse liver were mainly enriched in metabolic processes. Surprisingly, the downregulated genes in diabetic mouse liver were mainly enriched in immune-related processes, although all the altered genes were still mainly enriched in metabolic processes. Similarly, KEGG pathway analysis showed that metabolic pathways were the major pathways altered in diabetic mouse liver, and downregulated genes were enriched in immune and cancer pathways. Analysis of the key enzyme genes in fatty acid and glucose metabolism showed that some key enzyme genes were significantly increased and none of the detected key enzyme genes were decreased. In addition, FunDo analysis showed that liver cancer and hepatitis were most likely to be associated with diabetes. Taken together, this study provides the digital gene expression profile of diabetic mouse liver, and demonstrates the main diabetes-associated hepatic biological processes, pathways, key enzyme genes in fatty acid and glucose metabolism and potential hepatic diseases.

Show MeSH
Related in: MedlinePlus