PPARα-Target Gene Expression Requires TIS21^/BTG2 Gene in Liver of the C57BL/6 Mice under Fasting Condition

Area of Science:

• Molecular Biology
• Metabolic Research
• Gene Regulation

Background:

• The TIS21 (also known as BTG2/PC3) gene is part of the antiproliferative gene (APRO) family, known for tumor suppressive roles.
• While TIS21 is typically associated with cell proliferation control, its function under metabolic stress, such as fasting, remains less understood.

Purpose of the Study:

• To investigate the role of the TIS21 gene in regulating liver metabolism during fasting conditions.
• To identify the specific metabolic pathways and gene expression changes influenced by TIS21 deficiency under fasting.

Main Methods:

• Gene expression profiling using microarray analysis in TIS21 knockout (TIS21-KO) and wild-type (WT) mice after fasting.
• Immunohistochemistry and hematoxylin and eosin staining to assess liver morphology and lipid deposition.
• Quantitative analysis of specific gene expression, including peroxisome proliferator-activated receptor alpha (PPARα) targets, cathepsin E, and thioltransferase.

Main Results:

• TIS21-KO mice exhibited significantly reduced expression of PPARα target genes and increased lipid synthesis compared to WT mice during fasting.
• Histological analysis revealed focal lipid deposition in TIS21-KO livers versus diffuse deposition in WT livers after starvation.
• Cathepsin E expression was markedly upregulated, while glutaredoxin 2 thioltransferase expression was downregulated in TIS21-KO livers.

Conclusions:

• The TIS21 gene plays a critical role in maintaining liver energy metabolism and reducing power during fasting, primarily by controlling lipid metabolism rather than cell proliferation.
• Downregulation of glutaredoxin 2 thioltransferase in TIS21-KO livers may contribute to hypoxic damage.
• TIS21 is essential for normal metabolic adaptation to fasting states.