TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases

Abstract

Nonalcoholic fatty liver disease (NAFLD) is found in up to 30% of the world’s population and can lead to hepatocellular carcinoma (HCC), which has a poor 5-year relative survival rate of less than 40%. Clinical therapeutic strategies are not very successful. The co-occurrence of metabolic disorders and inflammatory environments during the development of steatohepatitis thus needs to be more specifically diagnosed and treated to prevent fatal HCC development. To improve diagnostic and therapeutic strategies, the identification of molecules and/or pathways responsible for the initiation and progression of chronic liver disease has been explored in many studies, but further study is still required. Transmembrane 4 L six family member 5 (TM4SF5) has been observed to play roles in the regulation of metabolic functions and activities in hepatocytes using in vitro cell and in vivo animal models without or with TM4SF5 expression in addition to clinical liver tissue samples. TM4SF5 is present on the membranes of different organelles or vesicles and cooperates with transporters for fatty acids, amino acids, and monocarbohydrates, thus regulating nutrient uptake into hepatocytes and metabolism and leading to phenotypes of chronic liver diseases. In addition, TM4SF5 can remodel the immune environment by interacting with immune cells during TM4SF5-mediated chronic liver diseases. Because TM4SF5 may act as an NAFLD biomarker, this review summarizes crosstalk between TM4SF5 and nutrient transporters in hepatocytes, which is related to chronic liver diseases.

Glucose‐mediated mitochondrial reprogramming by cholesterol export at TM4SF5‐enriched mitochondria‐lysosome contact sites

“…This suggests that TM4SF5 itself might drive the close membranous apposition between mitochondria and lysosomes in the presence of excessive extracellular glucose. For this to occur, TM4SF5, like other tetraspanins, has molecular characteristics for massive protein‐protein complex formation and subcellular translocation [ 3 , 45 , 46 ]. There can thus be different proteins in proximity to the TM4SF5‐FKBP8 linkage at TM4SF5‐enriched MLCSs, such as cholesterol transporters, mitophagy receptors, and mitochondrial dynamics‐related proteins.…”

Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease and Disease Treatment

“…Nonalcoholic fatty liver disease (NAFLD) is found in a high number of people and seems to be associated with the development of hepatocellular carcinoma (HCC). Since the transmembrane 4 L six family member 5 (TM4SF5) is a possible biomarker for NAFLD, the review by Kim et al [ 3 ] summarizes the relationships between TM4SF5 and other nutrient transporters in hepatocytes, which can be important in the development of chronic liver diseases.…”