Heme (dys)homeostasis and liver disease

Abstract

Heme is essential for a variety of proteins involved in vital physiological functions in the body, such as oxygen transport, drug metabolism, biosynthesis of steroids, signal transduction, antioxidant defense and mitochondrial respiration. However, free heme is potentially cytotoxic due to the capacity of heme iron to promote the oxidation of cellular molecules. The liver plays a central role in heme metabolism by significantly contributing to heme synthesis, heme detoxification, and recycling of heme iron. Conversely, enzymatic defects in the heme biosynthetic pathway originate multisystemic diseases (porphyrias) that are highly associated with liver damage. In addition, there is growing evidence that heme contributes to the outcomes of inflammatory, metabolic and malignant liver diseases. In this review, we summarize the contribution of the liver to heme metabolism and the association of heme dyshomeostasis with liver disease.

Keywords: ferroptosis; heme; hemolysis; immune response; iron metabolism; liver cancer; liver disease; porphyria.

FIGURE 1

The liver plays a central role in heme metabolism. The liver is tightly involved in all stages of heme metabolism, from its biosynthesis to its breakdown, and recycling of heme iron. About 15% of heme daily production occurs in hepatocytes, where the heme biosynthetic pathway is mainly regulated by the isoform 1 of the rate-limiting enzyme ALAS (ALAS1), which is feedback regulated by heme. Moreover, reticuloendothelial macrophages of the liver are vital to clear senescent RBCs by phagocytosis. RBCs-derived heme is transported from the phagolysosome to the cytoplasm by HRG1, then catalyzed by HMOX and the resulting ferrous iron (Fe2+) is either retained in ferritin molecules or exported through FPN1 and recycled for production of new RBCs in the bone marrow. Hepatocytes are also responsible for production of Hp and HPX, which bind to Hb or free heme, respectively, targeting them to CD163⁺ liver macrophages or LRP/CD91⁺ hepatocytes and Kupffer cells. These molecular scavengers reduce heme oxidative reactivity and subsequent cytotoxicity, preventing organ damage. Created with BioRender.com. ALA, 5-aminolevulinic acid; ALAD, Aminolevulinic acid dehydratase; ALAS1, Aminolevulinic acid synthase-1; BACH1, BTB and CNC homology 1; CO, Carbon monoxide; CPOX, Coproporphyrinogen III oxidase; FECH, ferrochelatase; FLVCR1b, Feline leukemia virus subgroup C receptor-protein; FPN1, Ferroportin; Hb, Hemoglobin; HMOX1, heme oxygenase 1; Hp, Haptoglobin; HPX, Hemopexin; HRG1, Heme-responsive gene-1; NRF2, Nuclear factor erythroid 2-related factor 2; PBGD, Porphobilinogen deaminase; PPOX, Protoporphyrinogen oxidase; RBC, Red blood cell; ROS, Reactive Oxygen Species; UROD, Uroporphyrinogen decarboxylase; UROS, Uroporphyrinogen synthase.

FIGURE 2

Heme dyshomeostasis is associated with liver disease. (A) In sickle cell disease, RBCs are more fragile and break apart during circulation, releasing significant amounts of heme and heme-enriched membrane microparticles. Such amounts of cell-free heme in circulation activate endothelial cells via ROS production and promote abnormal RBC adhesion, originating clumps that can block blood flow. This vascular occlusion may occur in liver sinusoids, preventing liver oxygenation and thus causing severe tissue damage. (B) Heme is a danger-associated molecular pattern (DAMP) that can modulate different cells in the immune compartment. Heme can activate innate immune receptors (e.g., TLR-4) and neutrophil NET formation, activating and amplifying inflammation. In turn, heme may inhibit dendritic cell maturation or modulate HMOX1 expression in monocytes, favoring T_reg expansion and macrophage M2 polarization. These anti-inflammatory responses are of the utmost importance in sterile liver inflammation or liver transplantation. Heme can also increase the expression of heme-inducible HMOX1 in immature neutrophils, inhibiting a proper oxidative burst in resulting mature neutrophils, thereby preventing host defense against pathogens targeting different organs, including the liver. (C) Cell-free heme, released during hemolysis, may promote metabolic liver disease by disruption of hepatic lipid metabolism. Hemolysis has been shown to promote lipid accumulation and block intracellular breakdown of lipid droplets by lipophagy, resulting in liver steatosis, a well-known trait of MAFLD. Heme-iron may also initiate lipid peroxidation, mediating the death of hepatocytes by ferroptosis, which potentially plays a role in the progression of MAFLD to NASH. (D) Enzymatic defects in the heme biosynthetic pathway result in metabolic disorders known as porphyrias, due to accumulation of different heme precursors (i.e., porphyrins), some of which are genotoxic. Their accumulation is associated with an increased risk of carcinogenesis. Created with BioRender.com. HMOX1, heme oxygenase 1; KC, Kupffer cell; LSEC, Liver sinusoidal endothelial cell; MAFLD, Metabolic dysfunction-associated fatty liver disease; NASH, Non-alcoholic steatohepatitis; NET, Neutrophil extracellular trap; NF-kB, Nuclear factor kappa B; NO, nitric oxide; RBC, Red blood cell; ROS, Reactive Oxygen Species; SC, Stellate cell; TLR-4, Toll-like receptor 4; T_reg, Regulatory T cell.