The Hepatocyte

The Hepatocyte

A liver-detoxifying cell

• Hepatocytes are the predominant cell type in the liver. An estimated 80% of the liver mass is made of these cells.
• directly exposed to the blood passing though the organ, by being in close contact with the liver blood sinusoids. The sinusoids carry blood from the edges of the lobule to the central vein.
• The hepatocytes are cuboidal in shape containing a nucleus (sometimes more than one) and an abundance of cellular organelles associated with metabolic and secretory functions.
• A few of these functions include...
• form and secrete bile
• store glycogen and buffer blood glucose
• synthesize urea
• metabolize cholesterol and fat
• synthesize plasma proteins
• detoxify many drugs and other poisons
• process several steroid hormones and vitamin D

The liver plays several roles in detoxification:

• it filters the blood to remove large toxins
• synthesizes and gets rid of bile full of cholesterol and other fat-soluble toxins

enzymatically eliminates unwanted chemicals

The enzymatic process to dispose of toxins occurs in two phases:

phase 1 (Oxidations)

• neutralizes the toxin or changes the toxic chemical to form activated intermediates

Ex: glutathione (GHS) is oxidized to glutathione disulfide (GSSG).

phase 2 (Conjugation)

• liver cells add another substance such as cysteine, glycine, or a sulphur molecule to a toxic chemical to make it less harmful.

As a result it makes the toxin water-soluble so that it may then be excreted from the body via watery fluids such as bile or urine.

The four organelles that work together to perform detoxification in hepatocytes

1. Smooth Endoplasmic Reticulum

2. Rough Endoplasmic Reticulum

3. Peroxisomes

4. Mitochondria

Well, what if one of these organelles malfunctioned? OR did not even occur in the cell?

• Without the sER, which must metabolize both naturally and externally produced toxins 24/7, a cell would quickly die if this function was not carried out.
• Liver disease (such as hepatitis or cirrhosis) can occur if the peroxisomes and their enzymes do not break down fatty acids, killing the ER and therefore the hepatocytes one by one due to a buildup of fatty acids.
• An increase in the volume density of SER is expected in the presence of intoxicating levels of ethanol.
• Hepatocytes in the alcoholic liver accumulate large amounts of fat and often become distended beyond recognition. By electron microscopy, mitochondria appear grossly enlarged, with a bizarre shape, and smooth endoplasmic reticulum is distended.
• Altered mitochondrial functions have been documented in a variety of chronic liver diseases including alcohol-induced liver disease, nonalcoholic fatty liver disease, viral hepatitis, primary and secondary cholestasis, hemochromatosis, and Wilson's disease.
• Due to impairment of the electron transport chain and/or oxidative phosphorylation
• leading to decreased oxidative metabolism of various substrates, decreased ATP synthesis, and reduced hepatocyte tolerance towards stressing insults.
• Functional impairment of mitochondria is often accompanied by structural changes, resulting in organelle swelling and formation of inclusion in the mitochondrial matrix. Adequate mitochondrial functions in hepatocytes are maintained by mitochondrial proliferation and/or increased activity of critical enzymes.
• Albumin, a major product of rough ER, maintains plasma

osmotic pressure. A decrease of Albumin causes edema and

ascites.

Sources:

• http://www.siumed.edu/~dking2/erg/gicells.htm#hepato
• http://www.madsci.org/posts/archives/1997-12/878404205.Cb.r.html
• http://www.bscb.org/?url=softcell/er
• http://www.livestrong.com/article/206335-peroxisomes-functions-in-liver-cell/
• http://www.meddean.luc.edu/lumen/MedEd/orfpath/cytopl.htm
• http://www.ganbing.com.cn/YLW22.htm
• http://www.histology.leeds.ac.uk/digestive/liver_hepatocyte.php
• http://www.ncbi.nlm.nih.gov/pubmed/21269263
• http://www.hindawi.com/journals/bri/2012/387626/
• http://www.sciencedirect.com/science/article/pii/S1740676510000052

Smooth ER

Peroxisomes

Mitochondria

(sometimes referred to as microbodies)

Rough ER

General Function:

• The rough ER working with membrane bound ribosomes takes polypeptides and amino acids from the cytosol and continues protein assembly including, at an early stage, recognizing a 'destination label' attached to each of them.

Specialized Liver Function:

• They produce blood plasma proteins, which are essential for clotting, osmotic pressure, and immunity.
• examples of which are albumin, fibrinogin, prothombin

General Function:

• manufacture and metabolism of lipids
• detoxifying a number of organic chemicals converting them to safer water-soluble products.

Specialized Liver Function:

• contains enzymes involved in the degradation and conjugation of toxins
• also responsible for synthesizing cholesterol and the lipid portion of lipoproteins and converting glycogen to glucose (glycogenolysis).
• Under conditions of challenge by drugs, toxins or metabolic stimulants, the sER becomes the predominant organelle.
• Stimulation by one drug, eg. alcohol, enhances its ability to detoxify some other compounds. On the other hand, some toxins can get metabolized to even more damaging compounds.

***smooth ER can double its surface area within a few days, returning to its normal size when the assault has subsided***

• The hepatocytes convert this to bilirubin, an iron depleted form of haem. The sER conjugates bilirubin to glucoronic acid, to make it water blood and some tissues, giving the skin a yellow colour known as jaundice.

General Function:

• generate hydrogen peroxide in detoxification reactions
• contain several enzymes to speed up specific cellular reactions
• buds off of endoplasmic reticulum (as opposed to Golgi, like lysosomes do)

Specialized Liver Function:

• To detoxify blood, they transfer hydrogen from the ethanol or alcohol molecules to oxygen (oxidation), using the enzyme catalyst peroxidase to facilitate this reaction.
• Peroxisomes also contain enzymes that convert the hydrogen peroxide (product of fatty acid oxidation) into water by removing a single oxygen atom from each molecule of hydrogen peroxide, using the enzyme called catalase for this reaction.
• Breakdown (by oxidation) of excess fatty acids.
• Breakdown of excess purines (AMP, GMP) to uric acid.

General Function:

• Power plant of the cell that generates ATP to perform required intracellular metabolic functions

Specialized Liver Function:

• essential in performing fatty acid oxidation, which regulates the flux of metabolites in the cell in order to adjust energetic demand, ammonia detoxification, or anabolic pathways.
• unique site for metabolizing ammonia into the less toxic urea.
• provides shuttle proteins that allow specific addressing to anabolic pathways, as in the case of citrate transport protein (CTP)
• hub that integrates hepatic metabolism of carbohydrates, lipids and proteins.
• essential in hepatocyte survival as mediator of apoptosis and necrosis.
• developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions
• in particular regulating organelle biogenesis and degradation

The body takes in ethanol (C2H60)

Ethanol is oxidized to acetylhyde

• Catalyzed my alcohol dehydrogenase, containing the coenzyme,NAD+
• One NAD+ is converted to NADP

Acetaldehyde is oxidized to acetate by the mitochondrial enzyme Acetaldehyde dehyrgrogenase 2

Acetate is converted in the liver to Acetyle CoA by acetyle CoA Acetate 1

(one ATP converts to AMP)

Acetyle CoA is used for fatty acid synthesis

Peroxisomes