Homozygous mutations in the Glucagon receptor cause fatty liver in the absence of obesity

In a paper published in Diabetes, we report a family where three individuals developed early-onset fatty liver disease which can lead to cirrhosis. While this condition is commonly associated with obesity, the family members had a normal body weight; all other known causes of liver disease were excluded. Using whole exome sequencing, we found they carried homozygous loss-of-function mutations in the gene encoding the Glucagon receptor (GCGR). Glucagon is known to play a key role in regulating carbohydrate and lipid metabolism acting via its receptors in the liver. Using stem cells into which we introduced the patients’ mutations using CRISPR/Cas9 gene editing, we were able to make hepatocytes (liver cells), which we used to model the disease. We found that the hepatocytes carrying the GCGR mutations could not clear lipid as expected, causing it to accumulate, proving a causal link between the mutations and fatty liver disease in patients. In clinical studies, we found the patients had very high levels of FGF-21, a growth factor and marker of liver inflammation. Further work is needed to identify potential downstream targets of GCGR action which could provide new approaches to treatment for patients. Our results are also relevant for understanding how GCGR agonists and antagonists work. In clinical trials, people with type 2 diabetes treated with GCGR antagonists sometimes develop increased liver fat; some trials have been discontinued as a result. In contrast, trials of GCGR agonists have shown they reduce liver fat in people with obesity and steatotic liver disease. Our findings provide a mechanistic explanation for these observations.

You can read the paper here: https://doi.org/10.2337/db25-0209