Troglitazone induces expression of PPARgamma in liver

G F Davies1, R L Khandelwal, W J Roesler

  • 1Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.

Insights

Troglitazone increases peroxisome proliferator-activated receptor gamma (PPARγ) in liver cells. This induction may explain how troglitazone sensitizes the liver to insulin and improves hyperglycemia.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Hepatology

Background:

  • Troglitazone is an insulin sensitizer acting via peroxisome proliferator-activated receptor gamma (PPARγ).
  • PPARγ levels are often low in target organs like the liver, where other PPAR isoforms predominate.
  • The mechanism by which troglitazone sensitizes liver to insulin requires further elucidation.

Purpose of the Study:

  • To investigate whether troglitazone induces PPARγ expression in liver cells.
  • To determine if troglitazone alters the expression of other PPAR isoforms (α and β).
  • To explore the potential role of PPARγ induction in troglitazone's mechanism of action.

Main Methods:

  • Treatment of isolated rat hepatocytes with troglitazone and 15-deoxy-delta12,14-prostaglandin J2.
  • Analysis of PPARγ mRNA and protein levels via dose-dependent assays.
  • Administration of troglitazone-containing diet to rats and subsequent liver analysis.
  • Assessment of PPARα and PPARβ expression levels.

Main Results:

  • Troglitazone significantly increased PPARγ mRNA and protein levels in rat hepatocytes (3-4 fold induction).
  • 15-deoxy-delta12,14-prostaglandin J2, a PPARγ ligand, also induced PPARγ expression, while PPARα ligands had no effect.
  • Troglitazone administration to rats increased hepatic PPARγ expression.
  • Troglitazone did not affect the expression of PPARα or PPARβ isoforms in the liver.

Conclusions:

  • Troglitazone induces PPARγ expression in liver cells and in vivo.
  • This induction represents a reprogramming of hepatic PPAR isoform content.
  • PPARγ induction by troglitazone may contribute to its insulin-sensitizing effects and hyperglycemia amelioration in the liver.

Related Concept Videos

Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
Hormones Regulating Blood Glucose01:16

Hormones Regulating Blood Glucose

Insulin is released by beta cells of the pancreas when blood glucose levels are high. It facilitates glucose absorption and utilization in insulin-dependent cells with insulin receptors on their plasma membranes. Insulin promotes glucose uptake by increasing the number of glucose transport proteins in the cell membrane, allowing glucose to enter the cell. As a result, glucose utilization and ATP production are enhanced.
In addition to accelerating glucose uptake and utilization, insulin has...
Oral Hypoglycemic Agents: Biguanides and Glitazones01:26

Oral Hypoglycemic Agents: Biguanides and Glitazones

Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood glucose levels...
Oral Hypoglycemic Agents: Glinides01:06

Oral Hypoglycemic Agents: Glinides

Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively manages...
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...