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.

Keywords: TM4SF5; amino acid transporter; fatty acid transporter; glucose/fructose transporter; hepatocyte; inflammation; metabolism; nonalcoholic fatty liver disease; protein–protein interaction; steatohepatitis; tetraspan(in).

Figure 1

Working model for TM4SF5-mediated crosstalk between membrane proteins and receptors including various nutrient transporters. The N138 and N155 residues in the long extracellular loop (LEL, the 2nd extracellular loop) of TM4SF5 (197 amino acids) can be N-glycosylated, which is important for protein–protein associations. At various subcellular membranes, including plasma membranes and lysosomes, and even extracellular vesicles, TM4SF5, like the tetraspanins, associates with other membrane proteins and soluble proteins. Upon cellular needs for the metabolic regulations inside or outside cells, the TM4SF5-mediated protein complexes at T₅ERMs may play roles in the stabilization/expression, binding, trafficking, and/or (signaling or transporting) activity of the complex components, leading to differential effects on cellular functions.

Figure 2

Metabolic regulation by TM4SF5. TM4SF5 can alter the metabolism of lipids, glucose/fructose, and arginine, resulting in the development of various features of chronic liver diseases. (A) Depending on the acute or chronic fatty acid or the fat supply, TM4SF5 in hepatocytes may negatively or positively support the transport activities of the fatty acid transporters via associations with the transporters, respectively. In case of acute supply, hepatocyyte TM4SF5 expression appears to reduce the fatty acid trasporting activity of SLC27A2 and SLC27A5, leading to less fat accumulation in the cells, whereas chronic intake of excess fatty acids leads to TM4SF5-mediated nonalcholoic steatohepatitis due to increased fatty acid uptake and accumulation. (B) When excessive fructose is available, TM4SF5 in hepatocytes causes GLUT8 from endosomal membranes to move toward plasma membranes following its release from their interaction, leading to increased GLUT8-mediated fructose uptake and, eventually, de novo lipogenesis (DNL). (C) Depending on the availability of extracellular (and thereby lysosomal) L-arginine, TM4SF5 binds to and causes mTOR to be translocated to lysosomal membranes, where TM4SF5 localizes and also binds to the L-arginine transporter (SLC38A9, solute carrier family 38 member 9) at the lysosome. The binding affinity of L-arginine to TM4SF5 is greater than that to SLC38A9, leading to the sensing of physiological L-arginine levels in the lysosomal lumen, enough for the export of L-arginine via SLC38A9 to the cytosol. This causes mTOR and S6K1 activation and, eventually, HCC development. FATPs, fatty acid transport proteins; CD36, fatty acid translocase; SREBP1, sterol regulatory element-binding protein 1; GLUT, glucose transporter; mTORC1, mechanistic target of rapamycin complex 1.

Figure 3

TM4SF5-mediated liver disease development. Healthy livers can be injured by different stimuli, including excessive nutrients, leading to lipid toxicity and hepatocyte damage. Following chronic damage, components of the inflammatory environment, including TGFβ1, CCL, CCL5, etc., can induce TM4SF5 expression in hepatocytes. Enhanced TM4SF5 can play roles in the regulation of the immunometabolic pathway and activity, consequently leading to the development of nonalcoholic steatosis (NAFL) with increased lipid uptake and accumulation, nonalcoholic steatohepatitis (NASH) with further inflammation and immune cell infiltration, fibrosis with STAT3-mediated extracellular matrix (i.e., collagen type I, laminin γ2, etc.) deposition, and eventually, hepatocellular carcinoma (HCC) with increased expression levels of AFP (α-fetoprotein), FUCA (α-L-Fucosidase 1), CD34 (CD34 antigen), laminin γ2, etc. TM4SF5-positive HCC can have features of the epithelial–mesenchymal transition (EMT) and actin reorganization, increasing the metastatic potential through the promotion of migration and invasion. Each dotted arrow indicates TM4SF5-mediated effects on the pathological development or progression. SOCS1/3, suppressor of cytokine signaling 1/3; STAT3, signal transducer and activator of transcription 3; SIRT1, Sirtuin 1; SREBPs, sterol regulatory element binding proteins; CCL2/5, C-C motif chemokine ligand 2/5; TGFβ1, transforming growth factor β1.

Figure 4

Working model for TM4SF5-dependent crosstalk between hepatocytes and immune cells during nonalcoholic fatty liver disease progression. (A) TM4SF5-dependent M1-type MF polarization and activation results in the secretion of proinflammatory cytokines, such as IL-6, which, in turn, enhances the expression of CCL20 and CXCL10 in TM4SF5-positive hepatocytes. Eventually, via chronic bidirectional crosstalk, reprogramming of M1-type MFs to M2-type MFs can occur during the progression to fibrosis and hepatocellular carcinoma. (B) High expression of TM4SF5 in liver cancer cells downregulates stimulatory immune checkpoint ligands and receptors on hepatocytes and NK cells, respectively, eventually leading to inhibited NK cell cytotoxicity. The downregulation of the stimulatory ligands and receptors may be achieved at the transcriptional level, since mRNA levels in NK cells depending on hepatocyte TM4SF5 expression are reduced in parallel with intracellular ERK1/2 signaling activity [13]. Alternatively, the modulation of the expression levels may also be a matter of protein stability according to TM4SF5-mediated associations and intracellular translocalization. IL6, interleukin 5; CCL20, C-C motif chemokine ligand 20; CXCL10, C-X-C motif chemokine ligand 10; MICA and MICB, MHC class I chain-related protein A and B; SLAMF6 and 7, signaling lymphocyte activation molecule 6 and 7; NKG2D, NKG2-D-activating NK receptor; IL6R, IL6 receptor; TM4SF5, transmembrane 4 L six family member 5.