Insulin-like growth factor-binding protein 7 exacerbates inflammatory response and lipid metabolism imbalance in alcohol-associated liver disease

Abstract

Alcohol-associated liver disease(ALD), caused by excessive alcohol consumption, are often associated with inflammatory outbreaks and lipid deposition in the liver. The role of Insulin-like growth factor-binding protein 7 (IGFBP7), an important metabolic regulator, in ALD, its underlying regulatory mechanism, and its potential implication in anti-ALD therapies remain unknown.

We investigated the effects of IGFBP7 on hepatic inflammation and lipid metabolism disruption in a mouse model of ALD. Mice were fed by chronic ethanol feeding plus a single binge of ethanol feeding(chronic-plus-single-binge model). In addition, ethanol exposure modeling studies were performed on cultured hepatocytes to verify molecular correlations.

The results showed that IGFBP7 expression was significantly elevated in the livers of mice and hepatocytes after chronic ethanol exposure. Subsequently, the results of a study by specific knockout of IGFBP7(IGFBP7-cKO) in mouse hepatocytes and lentiviral silencing of IGFBP7 in vivo suggested that IGFBP7 deletion could improve liver function levels in alcohol-fed mice; It also attenuated the outbreak of hepatitis factor and the disorder of lipid metabolism in mice.Using RNA-seq sequencing of mouse liver tissue, we found that IGFBP7 affects several downstream metabolic signaling pathways, including PPAR, MAPK, FoxO, etc. Then, we used the PPARα plasmid in hepatocytes and discovered that overexpressing PPARα reversed the impact of IGFBP7 on lipid metabolism disorders in hepatocytes.

In conclusion, IGFBP7 deficiency in alcohol-associated liver disease alleviates the decline in liver function and the imbalance of lipid metabolism in mice, attenuates the inflammatory outbreak, and affects a variety of downstream lipid metabolism factors by regulating PPARα. Hence, IGFBP7 may be an effective therapeutic target in the treatment of ALD.