By Suraj Patel, M.D., Ph.D.
Suraj Patel, M.D., Ph.D.
In patients with obesity, the liver’s ability to regulate blood sugar can become dysregulated due to chronic inflammation. As a result, fat accumulates inside the liver, a condition called nonalcoholic fatty liver disease (NAFLD) and systemic insulin resistance develops. Left untreated, this can lead to diabetes and worsening liver disease.
While it is established that obesity triggers chronic liver inflammation, common anti-inflammatory treatments targeting cytokines have proven ineffective. So, UT Southwestern took a closer look to find a potentially targetable pathway to reduce liver inflammation and potentially lower a patient’s risk of developing NAFLD and diabetes.
Our researchers discovered that inhibiting the response of hepatic interferon regulatory factor 3 (IRF3) – a protein that regulates transcription of genes – in liver cells after diet-induced obesity can:
- Improve glucose homeostasis
- Reverse insulin resistance
- Protect against liver damage
About the Research
IRF3 increases glucose levels by activating the transcription of PPP2R1B, a component of an enzyme called serine/threonine phosphatase (PP2A). PP2A plays an important role in the regulation of many proteins. In the liver, it inhibits insulin signaling and triggers unchecked glucose production.
Obesity activates IRF3 in humans, which regulates the transcription of a set of inflammatory genes, one of which, PPP2R1B, was shown to positively associate with worsening insulin resistance and diabetes in patients with NAFLD.
Our researchers found that inhibiting IRF3 in liver cells alters the impact of obesity throughout the body:
- In mice on a high-fat diet: Ablation of IRF3 throughout the body protected against steatosis and dysglycemia. When IRF3 was removed only from the liver cells, dysglycemia improved but steatosis and bodyweight did not improve. Acute suppression of liver IRF3 in obese mice was able to reverse insulin resistance and restore glucose homeostasis.
- After bariatric surgery in humans: Patients with obesity and NAFLD had increased activation of IRF3 in their livers and increased expression of PPP2R1B, with reversal after bariatric surgery.
This research identifies the IRF3-PPP2R1B axis in the liver as a causal link between obesity-induced inflammation and abnormal blood sugar levels. Knowing this information, and with future research, it could be possible to develop a medication to target this pathway to reduce the metabolic dysfunction associated with obesity and NAFLD.