The liver and intracellular digestion: How liver cells eat!

Abstract

The liver plays a pivotal role in the turnover of macromolecules because: (i) it is supplied by the nutrientrich portal blood (ii) it has a unique anatomy which permits direct physical contact between sinusoidal blood and liver cells; (iii) it is the principal source of most serum proteins, and (iv) it is composed of several types of cells that contain receptors and other membrane specializations that optimize removal of circulating materials. Major cellular activities that contribute to such macromolecular turnover include synthesis, extraction, metabolism and excretion ( l ) , activities that may be included under the general term "cellular processing." Whereas the physiological importance of the synthetic activities of the liver has long been appreciated (a), hepatic degradative or digestive processes have not received the same attention, even though Schoenheimer (3) emphasized the importance of degradation relative to synthesis in his classic work over four decades ago. Studies in the last 10 years have shown that a heterogeneous array of materials can be processed in liver cells, the cells often releasing resultant degradative products into bile (4). Recently, we reviewed the vacuolar components of intracellular digestion and reintroduced the concept of "cellular gastroenterology" (5, 6), a concept originally suggested by Christian de Duve over 30 years ago when he discovered the lysosome (7-9). Indeed, a quite reasonable series of analogies can be made between the digestive tract of the cell and that of the whole organism, as will be fully discussed later. For these reasons, it seemed timely to summarize current knowledge concerning intracellular digestion in liver cells. Although a number of recent reviews addressing specific mechanisms and regulatory aspects of intracellular digestion are available (10-19), none has been written from the unique perspective of the experimental hepatologist. Thus, the purpose of this overview is not to itemize further the available detailed information on intracellular digestion which has been covered extensively in preof Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905. vious reviews; rather, we intend to update and reorganize information on selected aspects of intracellular digestive processes in relation to experimental and clinical hepatology. We will place particular emphasis on the intracellular degradation of proteins ( i e . proteolysis) by hepatic parenchymal cells, since 99% of cellular proteins in the liver reside in hepatocytes (18,20) and since protein breakdown has been more extensively studied than the intracellular digestion of lipids and carbohydrates. We will also focus on lysosomes (i.e. ubiquitous intracellular organelles containing over 50 hydrolytic enzymes capable of degrading virtually all cellular constituents) because of our ongoing interest in these organelles and because they represent the best-characterized intracellular compartment for proteolysis. It should be added that many of the processes described in this review...

Liver Architecture

“…Lyso somes that are involved in the degradation of endogenous material are called auto phagic; others that degrade exogenous mate rial are heterophagic. In hepatocytes, the ly sosomes take part in a number of different autophagic processes [29], Recent studies suggest that more than 80% of total auto phagic proteolysis by hepatocytes is accom plished in lysosomes [30], but cellular diges tion processes can also be carried out on nonlysosomal pathways [31]. The primary lysosomes originate from the Golgi apparatus or, more precisely, the GERL, a complex related to the inner aspect of the Golgi stack containing a specialized region of smooth endoplasmic reticulum that forms the /ysosomes [32], According to Loud [28], the distribution pattern of lyso somes suggests a trend toward greater num the hépatocytes and especially at the biliary poles; it is assumed that the pericanalicular network of microfilaments constitutes the molecular basis of bile canaliculus move ments [35].…”

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

“…After binding of the ligand to the receptor, coated pits are formed that are internalized as coated vesicles. These vesi cles are uncoated, acidified and subse quently fuse with primary lysosomes, where the protein is degraded [115,119,120], A large number of receptor-mediated pro cesses have been identified on hepatocytes, endothelial cells and Kupffer cells. On hepato cytes one finds the asialoglycoprotein (ASGP) receptor, recognizing galactose and N-acetylgalactosamine-terminated glycoproteins [67,97,[115][116][117], a receptor for plgA (called se cretory component) [116], in addition to re ceptors for high-density lipoprotein particles [97], epidermal growth factor [116], transfer rin [119], hemopexin, chylomicron remnants, hemoglobin, insulin and peptide hormones [ 121 ], as well as for lysosomal proteases (after complex formation with a2-macroglobulins) [67,114], The Kupffer and endothelial cells also contain several sugar-recognizing recep tors, different from those present on the hepa tocytes [2,67,97,114,116,122].…”

Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium.

“…Proteolysis may be lysosomal or nonlysosomal. Because lysosomal proteolysis can be expected to be suppressed during ATP depletion and cell injury (54,55), it is reasonable to assume that calcium-dependent, nonlysosomal proteolysis contributes to lethal cell injury by GCDC. Indeed, an increase in calcium-dependent nonlysosomal proteolysis has been described as a mechanism for lethal hepatocellular injury by cystamine (53).…”