The Heme and Liver

## Bilirubin Transport and Albumin: Bilirubin, a byproduct of the breakdown of heme from red blood cells, is hydrophobic (non-polar) and cannot travel freely in the aqueous environment of the blood. To facilitate its transport in the bloodstream, bilirubin binds to albumin, a protein that helps increase its solubility. Albumin acts as a carrier for bilirubin, keeping it soluble and preventing its accumulation in tissues. Bilirubin in the blood is always bound to albumin, which keeps it in a safe, non-toxic state while circulating. This complex (bilirubin-albumin complex) travels through the bloodstream towards the liver. As it approaches the liver, specifically at the sinusoidal surface, the bond between bilirubin and albumin is broken. Albumin, being a plasma protein, remains in the bloodstream to continue its role in maintaining osmotic pressure and transporting other molecules. The now "free" bilirubin, no longer bound to albumin, is quickly taken up by hepatocytes (liver cells). The hepatocytes then conjugate the bilirubin, making it water-soluble (polar), which allows it to be excreted in bile. ## Uptake of Bilirubin into Hepatocytes: Passive diffusion and receptor-mediated endocytosis: Bilirubin is taken up by hepatocytes primarily through receptor-mediated endocytosis, but some passive diffusion also occurs. Receptor-mediated uptake ensures efficient and regulated entry of bilirubin into the liver cells from the blood. Cytosolic transport and binding proteins: Once inside the hepatocytes, bilirubin reaches the cytosol. To prevent bilirubin from reversing its flow back into the bloodstream (reflux), it binds to polar carrier molecules within the cytoplasm. These carrier proteins are essential to keep bilirubin from becoming toxic or diffusing back into the blood. Cytoplasmic binding proteins: The three key proteins that bind bilirubin and facilitate its transport within the cytoplasm are: - Ligandin (also known as glutathione S-transferase), which binds bilirubin to keep it in a soluble form and prevent its re-entry into the blood. - Z protein, another binding protein involved in bilirubin transport. - Glutathione-S-transferase (GST), which also plays a role in protecting bilirubin and aiding its transport within the cell. Transport to the SER: These proteins guide bilirubin to the smooth endoplasmic reticulum (SER), where the process of conjugation (detoxification) occurs, converting bilirubin into its conjugated (water-soluble) form. In summary, these intracellular proteins not only prevent the reflux of bilirubin into the blood but also assist in its transport to the SER, where detoxification and conjugation take place. ## Conjugation of Bilirubin: **Detoxification and glucuronidation:** Conjugation is a critical detoxification process in the liver where non-polar, toxic substances are made more water-soluble. In the case of bilirubin, the conjugation process involves glucuronidation, which increases the polarity of bilirubin, allowing it to be excreted more easily. **Transport to the Smooth Endoplasmic Reticulum (SER)**: Unconjugated (free) bilirubin, which is non-polar and toxic, is transported to the smooth endoplasmic reticulum (SER) of hepatocytes, where the conjugation process takes place. Glucuronyl transferase enzyme: Inside the SER, unconjugated bilirubin binds to one or two molecules of glucuronic acid. This reaction is catalyzed by the enzyme glucuronyl transferase. The enzyme facilitates the formation of an ester bond between glucuronic acid and the propionic acid side chains of bilirubin. ## Types of conjugated bilirubin: - If only one glucuronic acid molecule binds to bilirubin, it forms bilirubin monoglucuronide, where only one of the two propionic acid side chains is conjugated. - If both propionic acid side chains bind to two glucuronic acid molecules, it forms bilirubin diglucuronide, which is the fully conjugated form. **Conjugated bilirubin: **Both bilirubin monoglucuronide and bilirubin diglucuronide are referred to as conjugated bilirubin. This form of bilirubin is water-soluble and can be excreted into bile. **End products and ratios:** The conjugation process typically results in about 80% of bilirubin being converted into bilirubin diglucuronide, with the remaining 20% in the form of bilirubin monoglucuronide. The ratio of diglucuronide to monoglucuronide is roughly 4:1. ## Secretion of Conjugated Bilirubin into Bile: The liver functions as both an endocrine and exocrine organ. As an endocrine organ, it secretes hormones and other substances directly into the bloodstream. As an exocrine organ, it secretes products externally into ducts. Endocrine secretion: The liver synthesizes and secretes various products into the blood, such as albumin, clotting factors, and hormone-binding proteins. These products are vital for maintaining blood volume, clotting, and hormone transport. Exocrine secretion: The liver also secretes externally into the d