2.

Fat accumulation

The normal adult human liver may have up to 5% of its mass as lipid.

All of the three major classes of lipids that accumulate in lesions (phospholipids, cholesterol,
and cholesterol esters) are water insoluble. Phospholipids and cholesterol esters are almost
mutually insoluble, but cholesterol, a crystalline solid at 37 degrees C, has considerable
solubility in phospholipid bilayers and cholesterol esters. In normal infant intima, cholesterol
is solubilized by phospholipid membranes.

Hepatic steatosis is defined as intrahepatic fat of at least 5% of liver weight. Simple

accumulation of triacylglycerols in the liver could be hepatoprotective; however, prolonged
hepatic lipid storage may lead to liver metabolic dysfunction, inflammation, and advanced
forms of nonalcoholic fatty liver disease and is a risk factor for progression into disease. Liver
steatosis is graded based on the percentage of fat within the hepatocytes: grade 0 (healthy,
<5%), grade 1 (mild, 5%-33%), grade 2 (moderate, 34%-66%), and grade 3 (severe, >66%)

The amount of fatty acid in the liver depends on the balance between the processes of delivery
and removal. The size of triglyceride droplets (macrovesicular or microvesicular) may be an
indication to the underlying cause of the accumulation. Usually 'fatty liver disease', is referring
to diseases that are characterized by predominantly large droplet steatosis (macrovesicular
steatosis), or mixed large and small droplet steatosis. Potential pathophysiologic mechanisms
for fatty liver include the following:
 Decreased mitochondrial fatty acid beta-oxidation
 Increased endogenous fatty acid synthesis or enhanced delivery of fatty acids to the liver
 Deficient incorporation or export of triglycerides as very low-density lipoprotein (VLDL)

The liver does not store TAG in normal conditions; however, in conditions as obesity or with
high fat/high carbohydrate intake, abnormal lipid metabolism leads to ectopic (out of organ)
hepatic lipid accumulation. Intrahepatic fat and visceral (intestine) fat are independently
associated with metabolic dysfunctions, insulin resistance, and could be directly associated with
the dyslipidemia associated with hepatic steatosis. Dyslipidemia and hyperglycemia are present
in approximately 60% of patients with fatty liver. Lipid accumulation in the liver is also
associated with lipotoxicity due to increased endoplasmic reticulum stress, mitochondrial
stress, and impaired mitophagy. In addition to the environmental factors, several genetic defects
have been shown to be associated with hepatic steatosis. Disorders in genes involved in fatty
acid uptake, hepatic TAG secretion, and fatty acid oxidation lead to hepatic steatosis.

3.DNA damage

Despite it remains unclear whether all DNA repair mutations are truly causal in driving
tumorigenesis, or are a byproduct of the malignancy, they are highly significant in disease
progression and treatment. Several studies have linked upregulation of DNA repair genes with
chemo- and radio-resistance in multiple tumor types and with the ability of tumors to
metastasize. Loss of DNA repair function is significant in cancer initiation, gain of function of
similar genes and re-activation of lost repair pathways is involved in disease progression.

Liver cancer is the sixth most common cancer overall but the third most frequent cause of
cancer death. Among primary liver cancers, hepatocellular carcinoma (HCC), is associated
with multiple risk factors, including hepatitis B and C virus (HBV and HCV) infection, alcohol
consumption, obesity, and diet contamination. HCC frequently arises in the context of chronic
injury and inflammation that promote DNA damage and chromosomal aberrations, which
trigger a prompt set of signaling events known as the DNA damage response (DDR) pathways
which coordinate DNA repair, cell cycle arrest, and ultimately cell death or senescence (process
of deterioration with age).

Five major mechanisms exist within the DDR system:

(1) base excision repair (BER),

(2) mismatch repair (MMR), that will affect base mismatches

(3) nucleotide excision repair (NER),

(4) homologous recombination (HR), will be at the origin of stalled DNA replication fork

(5) non-homologous end-joining (NHEJ) the most serious form of DNA damage, will creates
double-strand break (DSB)

Aberrations of DNA damage response may ravage genomic integrity, creating genomic
alteration and instability that will trigger hepatocarcinogenesis, and facilitate advanced HCC
development. They can accumulate and change the signal transduction network. Genomic
instability include telomere erosion, chromosome segregation defects, and alterations in the
DDR pathways, while genomic alterations mostly include coding nucleotide repeats associated
with microsatellite instability (MSI). Microsatellite alterations have been widely and frequently
reported, mainly when cirrhosis is associated with HBV infection.