barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
38 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 39
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
NOVEL MECHANISMS OF ALCOHOLIC STEATOHEPATITIS
Sophie Lotersztajn
Créteil, France
E-mail: sophie.lotersztajn@inserm.fr
KEY POINTS
• The clinical spectrum of alcoholic liver disease includes steatosis, alcoholic hepatitis, fibrosis,
cirrhosis and increased risk of hepatocellular carcinoma.
• Steatosis results from alterations of lipid metabolism driven by alcohol, including: (i) increased
delivery of free fatty acids in the liver originating from the adipose tissue (ii) enhanced de novo
hepatic synthesis of fatty acids and reduced fatty acid β-oxidation and (iii) reduced fat export
from the liver.
• Ethanol, ethanol metabolites and oxidative stress play a major role in alcohol-induced
hepatocellular injury. In addition, alcohol increases endotoxin levels that activate Kupffer
cells, initiating an inflammatory process that leads to massive inflammatory cell recruitment,
contributing to hepatocellular injury and fat accumulation.
• Newly identified promising strategies mainly focus on modulation of gut microbiota and reduction
of the inflammatory response (CXC chemokines, interleukin 17, the complement system), while
sparing liver regeneration. Promising targets include the receptors for endocannabinoids (CB1
and CB2), sirtuin activators, and adenosine receptors.
INTRODUCTION
Alcoholic liver disease is characterized by a broad histological spectrum that encompasses isolated fatty
liver (steatosis), steatohepatitis, fibrosis and ultimately cirrhosis (1). Fatty liver is the prevalent lesion foun in
90 % of excessive drinkers, and has long been considered innocuous. However, fat generates inflammatory
signals and reactive oxygen species that initiate progression to more severe forms of the disease. Alcoholic
steatosis is defined by the presence of fat droplets in hepatocytes and is the earliest response of the
liver to chronic alcohol abuse. Environmental and genetic factors, and comorbid conditions (viral hepatitis,
obesity, HIV…) accelerate progression to steatohepatitis, that occurs in about 20-40% of heavy drinkers.
Steatohepatitis is characterized by fatty liver together with inflammatory cell infiltration into the liver and
hepatocyte injury. Steatohepatitis is associated with inhibition of liver regeneration and triggers activation
of liver fibrogenesis that leads to cirrhosis in 15-20% of patients (1). Patients with severe alcoholic hepatitis
display a prolonged and intense inflammatory reaction and have a high risk of short-term mortality. Few
advances have been made in the management of patients with alcoholic liver disease and there is an
urgent need to identify novel therapeutic targets (1).
Considerable progress has been made within the last decade towards better understanding of the molecular
mechanisms underlying alcoholic liver disease progression, with the identification of complex interactions
between non parenchymal cells, immune cells and hepatocytes (2).
MOLECULAR MECHANISMS OF ALCOHOL-INDUCED STEATOSIS
Steatosis results from several alterations of lipid metabolism driven by alcohol, i.e: i) increased lipolysis of
peripheral fat stored in adipose tissue, that flows to the liver as nonesterified fatty acids; ii) combination of
altered metabolic pathways within hepatocytes, including enhanced de novo synthesis of fatty acids within
the liver (lipogenesis) and reduced fatty acid mitochondrial β-oxidation; iii) reduced hepatic fat export (3)
(Figure 1).
Alcohol-induced decrease in fatty acid oxidation. Alcohol is metabolized to acetaldehyde in hepatocytes
by alcohol dehydrogenase (ADH) and cytochrome P4502E1, and acetaldehyde accounts for most of the
toxic effects of alcohol. Acetaldehyde is subsequently converted to acetate by mitochondrial aldehyde
dehydrogenase (ALDH). Both ALD and ALDH use NAD+ as cofactor, producing an excess of reducing
equivalent NADH. The resulting decrease in the NAD+/NADH ratio leads to reduction of mitochondrial fatty
acid oxidation (3).
Acetaldehyde also decreases fatty acid oxidation via inhibition of PPARα, a nuclear receptor that control the
transcription of genes involved in fatty acid transport and oxidation. In addition, decrease in PPARα reduces
fat export by counteracting alcohol-induced decrease in microsomal triglyceride transfer protein, a protein
required for the assembly of VLDL prior to export (3).
Another mechanism by which acetaldehyde decreases fatty acid oxidation is via inhibition of AMP
protein kinase, an enzyme that enhances fatty acid oxidation by phosphorylating/inactivating acetyl CoA
carboxylase, leading to inhibition of carnitine palmitoyltransferase 1, a rate limiting enzyme for fatty acid
oxidation. Interestingly, AMP protein kinase is also a negative regulator of fatty acid synthesis, because
Acetyl CoA carboxylase is a rate limiting enzyme for fatty acid synthesis (also see below) (3).
Alcohol-induced fatty acid synthesis. Acetaldehyde increases lipogenesis via transcriptional/posttranscriptional
regulation of sterol regulatory element binding protein 1-c (SREBP-1c), a transcription factor
that regulate the expression key lipogenic enzymes. SREBP-1c is directly induced by acetaldehyde, or
indirectly via alcohol-induced endoplasmic reticulum stress and hyperhomocysteinemia. SREBP-1c is
also negatively controlled by AMPK, so that inhibition of AMPK by alcohol also contributes to enhanced
lipogenesis (3).
Alcohol-induced down regulation of factors that limit fat accumulation. In addition to inhibiting PPAR
alpha and AMPK, alcohol also down regulates activators of AMPK, such as the adipokine adiponectin and
the NAD+-dependent deacetylase sirtuin1.
MOLECULAR MECHANISMS OF ALCOHOL-INDUCED STEATOHEPATITIS
Clinical evidence point out the role of endotoxin, toll-like receptors, cytokines and chemokines and oxidative
stress in the pathogenesis of alcoholic fatty liver disease; molecular mechanisms have mainly been
delineated in experimental studies with rodents.
The innate immune system (Figure 2)
Kupffer cells. Compelling evidence indicate that Kupffer cells play a key role in the initiation and progression
of alcohol induced liver injury (4). Chronic alcohol exposure triggers gut dysbiosis and enhances gut
permeability, thereby increasing the serum level of gut-derived endotoxin (LPS) that correlates with disease
severity. LPS activates Kupffer cells following binding to Toll-like receptor 4 (TLR4). Alcohol also sensitizes
Kupffer cells to LPS by increasing oxidative stress, and primes Kupffer cells to respond to LPS by upregulating
a number of proinflammatory mediators, including cytokines (TNF, IL1) and chemokines (MCP-1,
CXC chemokines, IL8), that contribute to various steps of alcoholic liver disease progression, i.e hepatocyte
steatosis, inflammatory cell recruitement, hepatocyte injury and activation of fibrogenesis (Figure 2) (4, 5).
In addition, acetate may enhance cytokine release from Kupffer cells, via a mechanism involving acetylation
of histones (6). Finally, recent data also demonstrate that the complement system may also contribute to
alcohol-induced Kupffer cell activation and release of TNF-alpha, independently of LPS activation of TLR4
(7) .
Tumor necrosis factor-α (TNF-α) is considered as a major mediator of alcohol-induced liver injury, as
shown in a number of clinical studies, and on the basis of experimental data demonstrating the substantial
reduction of hepatic steatosis, liver inflammation and hepatocyte apoptosis in TNF-R1 deficient mice and
in rodents treated with TNF-α antibodies. However, anti TNF-α therapy of patients with alcoholic hepatitis
showed increased mortality, owing to a high rate of infectious events in these patients (1, 2, 4, 5).
Alcohol may also impair the antiinflammatory response and resolution of inflammation. Indeed, activated
Kupffer cells release antiinflammatory mediators with hepatoprotective properties, such as interleukin 10