TRPM2 Promotes Lipophagy Through TFEB and LAL in HFD-Fed Mice

Area of Science:

• Hepatology
• Molecular Biology
• Calcium Signaling

Background:

• Abnormal calcium (Ca2+) signaling contributes to lipid accumulation in steatotic hepatocytes, potentially driving non-alcoholic fatty liver disease (NAFLD).
• The specific Ca2+-permeable channels involved and their mechanisms in steatotic hepatocytes remain poorly understood.

Purpose of the Study:

• To investigate the role of the Ca2+-permeable channel TRPM2 in lipid metabolism within steatotic hepatocytes.
• To elucidate the molecular mechanisms by which TRPM2 influences lipid accumulation and NAFLD pathogenesis.

Main Methods:

• Established a mouse model of NAFLD using a high-fat diet.
• Compared liver fat accumulation, fibrosis, lipophagy, TFEB, and lysosomal acid lipase between TRPM2-knockout and wild-type mice.

Main Results:

• TRPM2 gene knockout exacerbated liver fat accumulation and fibrosis.
• TRPM2 knockout impaired hepatocyte lipophagy, reduced lysosomal abundance, and attenuated lysosomal/autolysosomal acidification.
• TRPM2 deficiency decreased TFEB expression and nuclear translocation, and reduced lysosomal acid lipase expression/activity.

Conclusions:

• TRPM2 deficiency impairs lipophagy by affecting TFEB and lysosomal acid lipase.
• TRPM2 plays a protective role against high-fat diet-induced liver steatosis and NAFLD.
• Targeting TRPM2 may offer a therapeutic strategy for NAFLD.