LOX-1 gene knockout improves metabolic dysfunction-associated steatohepatitis in mice

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a severe liver condition characterized by fat accumulation, inflammation, and cell damage.
• Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in recognizing oxidized low-density lipoprotein and its role in MASH progression requires investigation.

Purpose of the Study:

• To investigate the role of LOX-1 in the progression of metabolic dysfunction-associated steatohepatitis (MASH).
• To evaluate the therapeutic potential of targeting LOX-1 in MASH.

Main Methods:

• LOX-1 expression analysis in mouse models of liver disease using GEO datasets.
• Generation of LOX-1 knockout mice (Lox-1-/-) using CRISPR/Cas9.
• Assessment of MASH phenotypes, including liver enzymes, histology, lipid accumulation, and fibrosis markers, in wild-type and Lox-1-/- mice fed a Western diet.
• In vitro studies using LX-2 cells to examine LOX-1's effect on fibrogenic markers.
• Network pharmacology and PPI analysis to predict downstream pathways.

Main Results:

• LOX-1 mRNA was upregulated in mouse models of liver disease.
• LOX-1 knockout significantly ameliorated Western diet-induced MASH, reducing liver enzymes (ALT, AST), steatosis, inflammation, and fibrosis.
• LOX-1 knockout suppressed the expression of key fibrogenic genes (Acta2, Col1a1, Timp1) in vivo and in vitro.
• LOX-1 silencing in LX-2 cells reduced alpha-smooth muscle actin (α-SMA) expression, indicating reduced fibrogenesis.

Conclusions:

• LOX-1 plays a critical role in promoting MASH development and progression.
• Targeting LOX-1 through gene knockout demonstrates significant therapeutic potential for MASH.
• LOX-1 may represent a novel therapeutic target for managing MASH.