Finding the transcriptional basis of diet-induced obesity

Metabolic dysfunction-associated steatotic liver disease, a type of fatty liver disease, affects more than 30% of the global population. Eating a Western diet, with high fat and sugar content, can harm liver metabolism if left unchecked and can lead to liver disorders such as increased hepatic inflammation, fibrosis, fatty liver (steatohepatitis) or even liver cancer. Metabolic dysfunction–associated steatohepatitis, or MASH, characterized by excessive triglyceride accumulation in the liver and liver inflammation, is a rising global health burden.

A group of researchers at Northeast Ohio Medical University has found that the protein Forkhead transcription factor 3, or FOXA3, an important regulator of metabolism and growth in the liver, provides beneficial effects during MASH, and Western diet–induced obesity. Hepatic nuclear transcription factors, including FOXA3, can modulate liver development and metabolism and regulate homeostasis. Researchers have previously shown that FOXA3 is reduced in fatty liver diseases such as MASH.

A recent research study, published in the Journal of Lipid Research, by Raja Gopoju, Jiayou Wang and a team in Yanqiao Zhang’s lab at NEOMED, established the positive effects of overexpressing FOXA3 on obesity and steatohepatitis in Western diet–fed mice.

Using adeno-associated viruses, or AAVs, as vectors, the team injected AAV-ALB-FOXA3 to overexpress the protein in mice and showed that treated mice had reduced hepatic triglyceride accumulation and reduced body fat. They also found reduced inflammation, improved metabolic function and increased lipolysis and energy spending in Western diet–fed mice. Increased levels of FOXA3 hence conferred protection against obesity and MASH.

The researchers further found that these changes occur through elevated plasma bile acid levels, which led to the activation of Takeda G protein–coupled receptor 5, or TGR5, which promotes thermogenesis, and also by showing that the protective effects of FOXA3 overexpression are lost in mice lacking TGR5.

The same research group previously reported that increasing FOXA3 expression has protective effects during atherosclerosis by enhancing reverse cholesterol transport. However, scientists know less about the impact of FOXA3 in steatohepatitis and Western diet–induced obesity. These new findings add to our understanding of the mechanisms underlying diet-induced MASH.

“Our study has yielded promising results in reducing diet-induced obesity, which has far-reaching implications for mitigating the burden of liver diseases,” Gopoju, a co-first author of the study, said.

Zhang’s group is now investigating the effects of FOXA3 in other tissues and metabolic disorders.

“The available strategies to treat fatty liver diseases are not accessible to all. We believe our findings may pave the way for innovative treatment approaches for MASH,” Gopoju added.