# Cartilage Intermediate Layer Protein 2 Aggravates Hepatic Lipid Accumulation and Inflammation Through the IRE1α/XBP1 Pathway

## TL;DR

This study shows that CILP2 worsens liver fat buildup and inflammation by activating the IRE1α/XBP1 pathway, suggesting it could be a target for treating liver disease.

## Contribution

The study reveals a novel role of CILP2 in promoting MASLD through the IRE1α/XBP1 pathway.

## Key findings

- CILP2 overexpression increases lipid synthesis and inflammation in liver cells.
- CILP2 knockout reduces high-fat diet-induced liver fat and improves glucose metabolism.
- CILP2 activates the IRE1α/XBP1 pathway, and its effects are partially reversed by specific inhibitors.

## Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and inflammation play important roles in hepatic lipid accumulation. Although CILP2 has been implicated in lipid metabolism, its role in MASLD remains unclear. Hepatic steatosis was induced in mice by a high-fat diet in this study. CILP2 was overexpressed in mouse livers and in vitro hepatocytes using the Ad-CILP2 adenovirus. CILP2 KO mice were also used in the experiments. Liver tissues and hepatocytes were collected for further analysis. CILP2 expression was upregulated in steatotic liver tissue and hepatocytes. CILP2 overexpression upregulated genes related to fatty acid synthesis (Srebp-1c, Fasn, Acc, Scd1, and Cd36), promoted lipid accumulation, and elevated the expression of proinflammatory cytokines (Il6, Tnf, and Il1b). Conversely, CILP2 knockout reduced high-fat diet-induced hepatic steatosis and improved glucose metabolism. Mechanistically, CILP2 activated the IRE1α/XBP1 branch of the ER stress pathway, thereby promoting lipid synthesis and inflammation, effects that were partially alleviated by 4-PBA and STF-083010 treatments. Our findings indicate that CILP2 contributes to hepatic lipid accumulation and inflammation via the IRE1α/XBP1 pathway and may represent a potential therapeutic target for MASLD intervention.