Figure 1. Structure of connexin (Cx) proteins and their channels. Cx proteins consist of four transmembrane regions, two extracellular loops (EL1 and EL2), one cytoplasmic loop (CL), an intracellular carboxy (CT), and an amino terminus (NT). Oligomerization of six Cx proteins creates Cx hemichannels. Homomeric hemichannels are composed of six single types of Cx proteins, whereas heteromeric hemichannels gather different Cx species. Gap junctions arise from the interaction of two Cx hemichannels on adjacent cells. Identical Cx hemichannels build up homotypic gap junctions, whereas different Cx hemichannels generate heterotypic gap junctions.

Figure 2. Organization of hepatic lobules. Hepatocytes build hepatic cellular plates that diverge from the hepatic vein. Branches of the hepatic artery, hepatic portal vein, and bile duct form the portal triad. Branches of the hepatic artery and portal vein gather together in hepatic capillaries that supply blood to hepatocytes. After a bidirectional exchange of substances between these hepatic capillaries and hepatocytes, blood is drained to the central hepatic vein. The localization of hepatocytes in the hepatic lobule determines access to oxygen and nutrients, whereby hepatocytes are localized in the periportal, midlobular, or perivenous zone.

Figure 3. Polarization of hepatocytes. The part of the hepatocyte membrane that allows interaction with the sinusoids and the perisinusoidal space is called the basal or sinusoidal membrane. The part of the hepatocyte membrane facing bile canaliculi is called the canalicular membrane. Both sides of the hepatocyte membrane are strictly separated by tight junctions, gap junctions, and adherens junctions. This provides a physical barrier between the sinusoids and bile ducts that prevents the mixing of blood and bile.

Figure 4. Connexin (Cx) protein expression in parenchymal and non‐parenchymal cells of the liver. The most prominent Cx species is listed at the top. In hepatocytes, Cx32 is the main Cx species, while Cx43 is the most important Cx species in non‐parenchymal cells.

Figure 5. Role of gap junctions in liver‐specific functions. Connexin (Cx) proteins, in particular Cx32, and their channels are involved in physiological processes, such as biotransformation of xenobiotics (A), carbohydrate metabolism (B), bile production (C), and protein synthesis and secretion (D). On the one hand, Cx proteins are involved in bile production by being essential units to form a physical barrier between hepatic sinusoids and bile canaliculi, since Cx32 colocalizes with tight junctional proteins such as zonula occludens protein‐1 (ZO‐1). On the other hand, Cx26 and Cx32 are critical building blocks of gap junctions that allow the passage of calcium ions (Ca²⁺) between hepatocytes, which is essential to regulate the process of bile secretion. Cx32 and its channels also stimulate the secretion of albumin. Enhanced expression of Cx26 and Cx32, associated with induced gap junction communication, but knockdown of Cx43 promotes cytochrome P450 (CYP) activity. Cx32‐based gap junctions promote the propagation of hormonal signals, such as noradrenaline and glucagon, to initiate the release of glucose from the liver hepatocytes.

Figure 6. Role of gap junctions involved in the hepatic life cycle. During liver cell proliferation, connexin (Cx) protein expression levels and gap junction activity are altered (A). Increased expression of Cx26 proteins is seen until the onset of the S phase. Gap junction activity also increases in the G1 phase. The progression from the G1 to the S phase is linked with decreased levels of Cx26 and Cx32, and reduced gap junction activity. Cx43 phosphorylation occurs upon progression from the G0 phase. An apoptosis‐mediating role for Cx channels is linked with their ability to spread inositol triphosphate molecules (IP₃) and calcium ions (Ca²⁺) to neighboring cells (B). The liver cell differentiation process of oval cells toward hepatocytes is accompanied by a switch from Cx43 to Cx32 (C).

Figure 7. Connexin (Cx) expression, Cx hemichannel activity, and gap junction activity in various liver diseases. In many liver diseases, the expression of Cx26, Cx32, or Cx43 is altered. In general, while there is a decrease of Cx26 and Cx32, the opposite is observed for Cx43 in pathological situations. Cx32 and Cx43 hemichannel activity is increased in acute liver injury, non‐alcoholic steatohepatitis, and fibrosis. In contrast, gap junction activity is decreased in most liver diseases.