The epidemics of the major metabolic diseases type 2 diabetes and cardiovascular disease
are increasing worldwide and much effort is being undertaken to understand the pathogenesis
of these conditions. Both type 2 diabetes and cardiovascular disease share insulin
resistance as a common and important risk factor in their natural history. It is now
widely accepted that organ cross talk harbors many critical clues that help to better
understand the pathogenesis of insulin resistance. In this respect, several studies
recently showed that not the increase in body fat mass per se, but the accumulation
of fat in the visceral cavity and particularly in the liver, which are conditions
commonly accompanied by inflammatory processes, are responsible for the genesis of
insulin resistance (1–4).
NONALCOHOLIC FATTY LIVER DISEASE
Prevalence, pathogenesis, and progression.
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased worldwide,
affecting more than 25% of adults. In obese people and in patients with type 2 diabetes,
the prevalence has increased to more than 70%. In obese children, NAFLD is found in
23–53% (5).
Several mechanisms lead to fatty liver. First, expansion and inflammation of adipose
tissue results in adipose insulin resistance and increased lipolysis and thereby in
an elevated flux of free fatty acids into the liver. Second, an impaired hepatic fatty
acid oxidation and a decrease in proteins inducing lipid oxidation, e.g., adiponectin,
results in further accumulation of fat within the liver. Third, increased hepatic
de novo lipogenesis driven by hyperinsulinemia and increased carbohydrate intake elevate
the hepatic fat content. Fourth, impaired VLDL secretion exacerbates this process.
This stage is often referred to as benign steatosis. The overwhelming of lipid oxidation
capacity eventually occurs resulting in the generation of reactive oxidative species
(ROS), gut-derived signals (e.g., bacterial endotoxins, short-chain fatty acids),
inflammatory cytokines, and an imbalanced release of adipokines that then may result
in the advance of this condition toward more severe stages such as steatohepatitis,
fibrosis, and cirrhosis (5).
It is interesting that in the natural history of NAFLD about 60% of the subjects have
no change in their liver histology parameters during a follow-up period of 3.5 to
11 years and 13% even have an improvement. On the other hand, within the same period
of time, 28% of the subjects have a progression to liver damage as steatohepatitis,
fibrosis, or cirrhosis (5). This has resulted in the fields of gastroenterology and
hepatology that the terms “benign” and “malignant” are being used to separate these
hepatic consequences of NAFLD.
What justifies the modified use of these terms when it comes to metabolic diseases?
It is the emerging observation that NAFLD without any liver-specific consequences
is often already strongly associated with metabolic alterations, most importantly
with insulin resistance, which plays an important role in the pathophysiology of dyslipidemia,
type 2 diabetes, and cardiovascular disease. As most of the people with fatty liver
do not progress to advanced stages of liver diseases, yet are confronted with metabolic
diseases that involve hepatic signaling processes, this article focuses on the early
stages. Because fatty liver in animals and humans can also be found without these
metabolic disorders, which is another focus of this article, the terms “metabolically
benign” and “metabolically malignant” are being used to carefully describe these two
interesting conditions.
NAFLD as a risk factor for type 2 diabetes and cardiovascular disease.
Mainly driven by epidemiological studies, evidence accumulated that fatty liver, measured
by ultrasonography or estimated from elevated blood markers of fatty liver and hepatic
inflammation, is not only cross-sectionally associated with insulin resistance independent
of measures of adiposity in adults and children, but also predicts incident type 2
diabetes and cardiovascular disease (6–8). These findings indicate that fatty liver
is directly involved in the pathogenesis of these diseases. However, it may be that
it was not possible to precisely account for the exceptionally strong relationship
of fatty liver with visceral adiposity in these studies. Hence, the true pathogenic
factor in subjects with fatty liver may be visceral obesity. Furthermore, fatty liver
simply may be a consequence of elevated levels of insulin and glucose, which induce
de novo hepatic lipogenesis, and of circulating free fatty acids, all of which are
found in insulin resistance. If this was the only explanation for the observed relationships,
then fatty liver can serve as a very good marker of the elevated risk, e.g., in the
prediabetic state, but specifically targeting fat accumulation in the liver is not
a promising way when it comes to the prevention or treatment of type 2 diabetes or
cardiovascular disease.
Fatty liver as a cause of insulin resistance
Hepatic insulin resistance and hepatic inflammation.
However, data emerged indicating that fatty liver may indeed be an important cause
of insulin resistance. In hepatic steatosis, free fatty acid and triacylglycerol (TAG)
metabolites (fatty acyl-CoA, diacylglycerol [DAG], ceramides) accumulate. In particular,
DAG activates protein kinase C (PKC) isoforms, which were shown to phosphorylate serine
residues in insulin receptor substrate (IRS)-1/2, thereby inhibiting insulin signal
transduction and ultimately increasing hepatic glucose production (9). Furthermore,
fatty acids can induce intracellular inflammation by stimulating the nuclear factor-κB
(NF-κB) or by generating endoplasmatic reticulum (ER) and oxidative stress, mediated
by activation of c-Jun N-terminal kinase (JNK) 1. In this aspect, the saturated fatty
acid palmitate plays a major role. It was found to inhibit hepatocyte insulin signaling
via JNK activation. Interestingly, this appears to be mediated by increased β-oxidation
of palmitate resulting in increased electron flux in the mitochondrial respiratory
chain and increased ROS production (10), which is known to induce insulin resistance
(11). Thus, high mitochondrial oxidative phosphorylation, fueled by palmitate metabolism,
may induce ROS production and thereby insulin resistance. Moreover, predominantly
saturated fatty acids, ligands of the membrane-bound Toll-like receptor (TLR) 2 and
4, are thought to induce insulin resistance and inflammation virtually by the same
intracellular mechanisms without being converted to fatty acyl-CoAs (2).
Interestingly, recently data emerged showing that excessive mitochondrial free cholesterol
may be a major cause for the progression of steatosis to more severe forms of liver
disease (12). Furthermore, impaired hepatic protein metabolism is involved in the
pathogenesis of hepatic inflammation. In this respect particularly metabolism of methionine,
which is required for availability of the antioxidant glutathione and is a precursor
of s-adenosylmethionine, the key methyl donor for phosphatidylcholine synthesis that
is required for the export of VLDL triglycerides, is important (13). In addition,
lipopolysaccharides and other proinflammatory molecules such as flagellin, peptidoglycan,
or lipoproteins are increasingly found in the circulation as a result of altered gut
microbial composition and bind to TLRs (2) (Fig. 1). Thus, the close interaction of
immune cells with the metabolically active hepatocytes is thought to trigger local,
but also systemic subclinical inflammation.
FIG. 1.
Pathways involved in inflammation and metabolism in human fatty liver disease. Abundant
levels of glucose, fructose, and free fatty acids directly, and fatty acids and lipopolysaccharides
(LPSs) via TLR2 and 4 signaling, induce ER stress. Fatty acids and free cholesterol
are also thought to induce mitochondrial dysfunction and increase ROS production.
This results in the activation of inflammatory pathways involving JNK and IKK, which
then induce the transcription of inflammatory cytokines and consequently play a role
in the inhibition of insulin signaling via IRS1 and 2. By increasing hepatic de novo
lipogenesis (DNL), fatty acids, glucose, and fructose increase the DAG pool which,
through activation of PKCs, also impairs insulin signaling. IR, insulin receptor.
P, phosphorylation. MD-2, myeloid differentiation protein-2.
Hepatokines.
Important support for a role of fatty liver in the early stages of the pathogenesis
of insulin resistance then came from studies showing that mechanisms of fatty liver–induced
metabolic diseases may differ from those of expanded adipose tissue mass. The new
concept that we and other investigators propose is that the fatty liver releases factors
in the circulation, similarly to the expanded and inflamed adipose tissue (adipokines),
which can be called hepatokines, and that they have direct effects on target tissues.
In this aspect we carefully studied the protein fetuin-A, which is exclusively secreted
from the liver. Two decades ago fetuin-A was identified as a strong inhibitor of insulin
signaling (14). We and other investigators recently showed that fetuin-A strongly
induces inflammatory cytokine expression in monocytes and in mouse and human adipose
tissue, and that it decreases the expression of the insulin-sensitizing and anti-inflammatory
adipokine adiponectin (15,16). Furthermore, fetuin-A was found to be upregulated in
fatty liver in mice and in humans (17). Finally, variants in the fetuin-A gene (AHSG)
and circulating levels of fetuin-A predict both incident type 2 diabetes (18) and
cardiovascular disease (19) independently from other well-established risk-markers.
Importantly, using the Mendelian randomization approach allowed us to show that these
relationships are most probably causative (20). This supports an important and independent
role of fatty liver in the pathogenesis of these diseases.
In addition, sex hormone–binding globuline (SHBG), which was also shown to be exclusively
released from the liver and was found to be causally involved in the protection from
diabetes (21), was found to be suppressed in fatty liver in animals during increased
glucose and fructose-induced de novo lipogenesis and in humans (22).
More recently, Misu et al. (23) identified selenoprotein P, which is primarily produced
by the liver and serves as a selenium supply protein, to be upregulated in the liver
of patients with type 2 diabetes and to be associated with insulin resistance. Furthermore,
they could show that glucose and palmitate upregulate while insulin downregulates
selenoprotein P mRNA expression in cultured hepatocytes. Moreover, they provided proof
that selenoprotein P induces insulin resistance in vitro and in animals (23). Thus,
there is strong support for the hepatokines fetuin-A, SHBG, and selenoprotein P to
play an important role in the pathogenesis of insulin resistance and subclinical inflammation.
Finally, studies showing that liver fat content, much stronger than visceral fat mass,
determines insulin sensitivity in humans (3,4), support a direct and major role of
fatty liver in the pathogenesis of insulin resistance. As a result, there are now
worldwide efforts in the scientific field aimed at studying the impact of fat accumulation
in the liver as a cause for metabolic diseases.
Dissociation between fatty liver and insulin resistance
TAG synthesis and breakdown.
However, this may not be easy in the first instance. Mechanisms that are involved
in the development of impaired metabolic signaling and more severe hepatic stages
of NAFLD are not thought to be associated with increased TAG storage but increased
availability of hepatic fatty acyl-CoAs (24). Proof of this concept first emerged
from animal data suggesting that under certain conditions, dissociation between fatty
liver and insulin resistance is present. The liver-specific acyl:CoA:diacylglycerol
acyltransferase 2 (Dgat2) transgenic mouse had a fivefold increase in liver TAG content
compared with controls, however, it did not develop whole-body or hepatic insulin
resistance (25). DGAT2 catalyzes the final step and therefore the rate-limiting reaction
of TAG biosynthesis. It covalently joins a fatty acyl-CoA and a sn-1,2-DAG molecule
to form TAGs. This suggests that DGAT2 is responsible for incorporating endogenously
synthesized monounsaturated fatty acids into TAGs. Consequently, DGAT2 may protect
from fatty acid signaling and fatty acid toxicity. This hypothesis is supported by
the finding that on a high-fat diet, activation of JNK and NF-κB in Dgat2 transgenic
mice was not increased compared with controls (25).
Further support that TAGs represent a safe harbor for fatty acyl-CoAs was provided
from the adipose triglyceride lipase (Atgl)-deficient mouse model. Under a high caloric
diet, large amounts of lipids accumulated in several tissues, including the liver,
in these animals. However, compared with controls, these mice remained insulin sensitive
(26). In addition to the activity of lipases, the form of package of the lipids in
the liver is important. In this respect, the deficiency of perilipin, adipose differentiation–related
protein, tail interacting protein of 47 kd (PAT) proteins was found to result in a
large increase in hepatic lipid droplet (LD) size and a reduction in LD number. This
was accompanied by a 2.5-fold increase in the lipolytic rate with an increase of the
ATGL at the LD surface and by increased insulin resistance, as indicated by a decrease
in insulin-stimulated Akt phosphorylation (27).
Fatty acid pattern.
In hepatocytes, other mechanisms also protect from lipotoxicity. Mice deficient for
the elongation of long-chain fatty acids-6 (Elovl6) gene developed obesity and hepatic
steatosis, but not insulin resistance, hyperinsulinemia, or hyperglycemia under a
high-fat, high-sucrose diet (28). ELOVL6, which is induced by sterol regulatory element–binding
protein-1c, catalyzes the conversion of the saturated fatty acid palmitate (C 16:0)
to stearate (C 18:0) as well as the monounsaturated fatty acid palmitoleate (C 16:1n-7)
to vaccinate (C 18:1n-7), thus regulating the tissue fatty acid composition. In this
animal model, the expression of peroxisome proliferator–activated receptor (PPAR)-α
and PPAR-α target genes, which induce fatty acid oxidation, was reduced. Mechanisms
involved in this process resulting in hepatic steatosis are not known. Interestingly,
in the Elovl6-deficient mice, hepatic inflammatory processes were not altered. However,
liver-specific decrease in the activity of the DAG-PKCε pathway was found. As expected,
hepatic levels of the fatty acid palmitoleate, which protect from insulin resistance,
also were elevated in the Elovl6-deficient mice (28).
In addition, stearoyl-CoA-desaturase (SCD) 1, which converts saturated fatty acids
to less harmful monounsaturated fatty acids, is another interesting candidate involved
in the protection from lipotoxicity. While data in the literature about the role of
SCD1 in this process are not consistent, there is increasing evidence that SCD1, which
is involved in the channeling of toxic fatty acids into triglyceride pools, may prevent
lipotoxicity (29). In agreement with this hypothesis in animals, SCD1 deficiency under
a methionine- and choline-deficient diet was found to be associated with less hepatic
TAG accumulation compared with wild-type animals, however with increased hepatocellular
apoptosis and steatohepatitis (30).
Inflammation.
What about lipid-induced hepatic inflammation? It was shown that NF-κB transcriptional
targets are activated in the liver by obesity and a high-fat diet, resulting in a
chronic state of subacute inflammation and insulin resistance. Inhibition of NF-κB
activation under a high-fat diet, through expression of the dominant inhibitory IκBα,
then still resulted in hepatic steatosis, however this was not accompanied by insulin
resistance (31). Similar results were found by partial suppression of hepatic NF-κB
activation via inactivation of the NF-κB essential modulator gene NEMO (32). These
findings indicate that under conditions of inhibited NF-κB activation, fatty liver
does not result in hepatic inflammation and insulin resistance. Thus, inhibition of
hepatic inflammatory signaling may be a promising therapeutic tool to prevent and
treat metabolic consequences of fatty liver as hepatic insulin resistance. However,
caution is needed when doing this since recent advances in this field helped to understand
in more detail the complex system of hepatic cytokine signaling. In this aspect, it
was shown that mice with hepatic deficiency of interleukin-6 receptor a (IL-6Ra) unexpectedly
developed insulin resistance in liver, skeletal muscle, and white adipose tissue (33).
In addition, and again unexpectedly, ablation of JNK1 in hepatocytes resulted in glucose
intolerance, insulin resistance, and hepatic steatosis (34). Therefore, more knowledge
needs to be gathered prior to regulating different proposed proinflammatory signaling
pathways in humans.
In this respect, Kupffer cells represent interesting targets. Kupffer cells deriving
from circulating monocytes are involved in several hepatic processes including presentation
of antigens during viral infections of the liver, the removal of particulate material
from the portal circulation, the production of nitric oxide, and the generation of
several cytokines. Recently, Kupffer cell depletion by using clodronate liposomes
or gadolinium chloride in mice reduced hepatic steatosis, putatively mediated by upregulation
of hepatic lipid oxidation, involving decreased proinflammatory tumor necrosis factor
(TNF)-α and IL-1β signaling (35,36). In addition, Kupffer cell depletion was associated
with improvement of hepatic insulin sensitivity in mice and with reduced inflammatory
signaling, even without reducing hepatic steatosis (37). As a possible major mechanisms
by which Kupffer cells are involved in the genesis of hepatic inflammation and of
hepatic stellate cell activation and thus hepatic fibrosis, recently bacterial and
DNA-induced TLR9 signaling and increase in IL-1β was identified (38). This finding
again supports the important role of hepatic inflammation as a regulator of hepatic
lipid signaling.
When focusing on metabolic effects in the liver, the role of adipose tissue inflammation
needs to be taken into account. This is not only supported by the large body of evidence
regarding the regulation of adiponectin production and its effects on hepatic steatosis
and inflammation (39), but also by the evidence that adipose tissue JNK1 activation
induces hepatic insulin resistance, possibly by increasing IL-6 secretion (40). Interestingly,
in the aforementioned study, JNK1 deficiency in myeloid cells or in hematopoietic
cells resulted in reduced production of TNF-α and IL-6 from macrophages, however not
in protection from high-fat diet–induced insulin resistance. In contrast, hematopoietic
JNK1 (41), inhibitor of κB kinase (IKK-β) (42), and TLR4 (43) deletion in mice in
other studies was associated with prevention of hepatic and adipose tissue insulin
resistance. These data highlight the important role of the interaction of adipocytes
and hepatocytes with macrophages in the development of obesity-induced insulin resistance.
Human studies.
In contrast to animals, information about the existence of ectopic fat accumulation
in the liver, which is not accompanied by insulin resistance, dyslipidemia, or systemic
subclinical inflammation in humans, is scarce. However, data from human studies about
increased ectopic storage of fat in the skeletal myocyte, which is not accompanied
by insulin resistance, support the concept that TAGs represent a safe harbor for fat.
Kelley (44) elegantly showed that increase in physical activity does not necessarily
change the amount of intramyocellular lipid content but reduces the LD size, and this
correlates with an increase in insulin sensitivity. It was hypothesized that the smaller
LD size increases the surface area in relation to volume, possibly resulting in higher
rates of triglyceride turnover. Furthermore, a mobile skeletal myocyte TAG pool with
small, metabolically flexible LDs may help to maintain low concentrations of long-chain
fatty acyl-CoAs, DAG, and ceramide, and high insulin sensitivity in skeletal muscle
(44,45).
To study whether such dissociation also exists between fatty liver and insulin resistance
1) it has to be established that with increasing liver fat content, insulin sensitivity
deteriorates, and that this relationship is independent of other major determinants
of these phenotypes such as age, sex, and, in particular, visceral adiposity; 2) subjects
need to be identified who remain insulin sensitive, although fatty liver is present;
and 3) preferably genetic variability may explain this dissociation.
We performed these analyses with data from 337 subjects who participated in the Tübingen
Lifestyle Intervention Program (TULIP) and who underwent measurement of total body
and visceral fat by magnetic resonance (MR) tomography and liver and intramyocellular
fat content by 1HMR spectroscopy. Indeed, we found a strong negative correlation of
liver fat with insulin sensitivity estimated from the oral glucose tolerance test
(OGTT) (Fig. 2), even after adjustment for sex, age, and total body and visceral fat
mass. In addition, subjects could be identified who remained insulin sensitive while
fatty liver was present (Fig. 2). To investigate these relationships in more detail,
first we divided the individuals based on liver fat content into seven groups. Each
group was then divided by the median insulin sensitivity in insulin sensitive and
insulin resistant subgroups. Within each of the seven groups, the subgroups did not
differ in liver fat (all P ≥ 0.30). However, insulin sensitivity was lower, and the
prevalences of the metabolic syndrome and prediabetes or newly diagnosed diabetes
were higher in the insulin resistant compared with the insulin sensitive subgroups
(all P ≤ 0.0001) (Fig. 3A–D
). Interestingly, among individuals with fatty liver, 37% did not have the metabolic
syndrome, prediabetes, or diabetes. Furthermore, between the subgroups with fatty
liver, the parameters of age, sex, and total body, visceral, or intramyocellular fat
content were not different. In addition, circulating adiponectin and IL-6 markers
of adipose tissue inflammation in the resting and fasting state, which are associated
with insulin sensitivity independent of visceral fat and liver fat, were not different.
However, circulating plasminogen activator inhibitor-1, a putative marker of hepatic
inflammation (46), and levels of the hepatokine fetuin-A were higher in the insulin
resistant subgroups.
FIG. 2.
Relationship between liver fat and insulin sensitivity in humans. There is a strong,
negative relationship between liver fat content measured by 1HMR spectroscopy and
insulin sensitivity estimated from the OGTT (as proposed by Matsuda and DeFronzo [10,000/√(mean
insulin×mean glucose)×(fasting insulin×fasting glucose)]) after adjustment for sex,
age, and total body and visceral fat mass, here shown in 337 individuals (327 without
diabetes and 10 with newly diagnosed type 2 diabetes; regression line and 95% CI).
However for a very similar liver fat content, individuals can be identified who are
relatively insulin sensitive (green field) and insulin resistant (red field). AU,
arbitrary units.
FIG. 3.
Relationships of subgroups of individuals based on liver fat and the median insulin
sensitivity with liver fat, insulin sensitivity, prediabetes, and the metabolic syndrome.
We measured total body and visceral fat in 337 subjects by MR tomography, and liver
and intramyocellular fat by 1HMR spectroscopy. Insulin sensitivity was estimated from
the OGTT (as proposed by Matsuda and DeFronzo [10,000/√(mean insulin×mean glucose)×(fasting
insulin×fasting glucose)]). Participants were first divided into seven groups: quartiles
of liver in subjects without fatty liver (liver fat <5.56%, n = 225) and tertiles
of liver fat in subjects with fatty liver (liver fat ≥5.56%, n = 112). Each group
was then divided by the median insulin sensitivity in an insulin sensitive (IS) and
an insulin resistant (IR) subgroup. Within each of the seven groups, the subgroups
did not differ in liver fat (all P ≥ 0.30) (A). However, insulin sensitivity (B) was
lower and the prevalences of prediabetes (impaired fasting glycemia and/or impaired
glucose tolerance) or newly diagnosed diabetes (C) and the metabolic syndrome (National
Cholesterol Education Program Adult Treatment Panel III criteria) (D) were higher
in the IR compared with the IS subgroups (all P ≤ 0.0001). Arb., arbitrary.
Also in agreement with the animal studies, a single nucleotide polymorphism (SNP)
in DGAT2 in humans was found to be associated with fatty liver but not with insulin
resistance (47). Furthermore, such dissociation was detected in patients with familial
hypobetalipoproteinemia (48). So far, mechanisms explaining this relationship are
still unknown. The strongest evidence that hepatic TAG synthesis may represent a mechanism
involved in the detoxification of hepatic lipids came from genomewide association
studies. By far, the largest genetic impact on fatty liver in humans was found to
be provided by a SNP (rs738409) in the patatin-like phospholipase 3 gene (PNPLA3),
which is also known as adiponutrin. While the SNP was strongly associated with elevated
liver fat, it was not associated with insulin resistance, dyslipidemia, or subclinical
inflammation in adults (49–51). Consequently, for a similar liver fat content, the
fatty liver–associated G allele should be protective of metabolic consequences. This
hypothesis was supported in humans when increased insulin sensitivity in vivo and
absence of upregulation of hepatic TNF-α gene expression in human liver biopsies with
increasing TAG content was found in carriers of the G allele (50). If so, then according
to the current concept, G allele carriers also may be protected from more advanced
stages of hepatic diseases. However, in about 600 human liver biopsy samples, the
G allele not only associated with hepatic steatosis but also with indices of steatohepatitis,
fibrosis, and cirrhosis (52). Again, in the same population, the G allele was not
associated with an increased but with a decreased risk of type 2 diabetes and with
lower serum lipid levels and blood pressure.
What is known about general mechanisms of PNPLA3/adiponutrin action? PNPLA3 may have
lipogenic functions in adipose tissue and most probably also in the liver, thereby
increasing hepatic TAG synthesis. Furthermore, PNPLA3/adiponutrin has transacetylase
functions and uses DAG as an acyl acceptor. Therefore, increased activity of the protein
may also result in depletion of the hepatic DAG and the fatty acyl-CoA content, both
of which are involved in hepatic insulin resistance. Based on the recent findings
that carbohydrates and fatty acids increase PNPLA3 protein levels in liver cells (53),
PNPLA3 may rather have a more important role in lipid remodeling than lipid catabolism.
The further investigation of the impact of the rs738409 SNP in PNPLA3 on the different
zones of the hepatic acinus, as already shown for steatosis (52), will help to clarify
the role of PNPLA3 in hepatic functions and ultimately may help to unravel mechanisms
involved in the putative dissociation of hepatic metabolic signaling and processes
related to liver damage.
CONCLUSION
Fatty liver may have an important role in the pathogenesis of the major epidemically
spreading metabolic diseases: type 2 diabetes and cardiovascular disease. This hypothesis
is supported by previous findings about the role of hepatic fat accumulation in the
promotion of a metabolically malignant condition that is characterized by dyslipidemia
and increased hepatic glucose production. Furthermore, it is supported by the recent
data showing that fatty liver–derived proteins—hepatokines—are directly involved in
the pathogenesis of both diseases. However, recent in vitro animal and human data
unexpectedly revealed that under certain conditions fatty liver is not accompanied
by such adverse events but is associated with a metabolically benign state. Mechanisms
explaining these novel findings are effective hepatic TAG synthesis, lipid desaturation,
and inhibition of lipid-induced inflammatory signaling. In particular, hepatic TAG
synthesis is now recognized as an adaptive process in situations when TAG precursors
are abundant and allows storage of lipids in their least toxic form. However, when
these compensatory mechanisms are overwhelmed, fatty acids induce damage to cells
resulting in impairment of metabolism (Fig. 4). Hence, targeting mechanisms involved
in a safe cellular storage of lipids may provide promising approaches to prevent and
treat type 2 diabetes and cardiovascular disease besides also inducing lipid oxidation
and inhibiting inflammatory signaling. Furthermore, there is exciting emerging data
indicating that hepatic metabolic signaling and mechanisms involved in the process
of hepatic steatohepatitis, fibrosis, and cirrhosis may differ. Thus, future research
in this field, including studies applying a translational approach to investigate
the impact of novel identified hepatic mechanisms in vitro and in animals and their
role in humans, may be able to teach us about yet unknown mechanisms involved in the
pathogenesis of metabolic diseases.
FIG. 4.
Cause and metabolic consequences of fatty liver. Hyperglycemia and hyperinsulinemia
induce hepatic de novo lipogenesis via carbohydrate response element–binding protein
(ChREBP) and sterol regulatory element–binding protein (SREBP)-1c, respectively, thereby
increasing the hepatic pool of fatty acyl-CoAs. This pool is also increased by augmented
delivery of free fatty acids (FFAs) either through the diet or lipolysis in adipose
tissue. Fatty acyl-CoAs are assembled to TAGs that remain in the liver or are secreted
in the form of VLDLs. The latter pathway is regulated by several factors, among them
the two enzymes SCD1 and DGAT2 as well as the microsomal transfer protein (MTP) and
the availability of apoliprotein B (ApoB). ELOVL6 and PNPLA3/adiponutrin are also
involved in the process of hepatic TAG storage, while specific mechanisms of action
are not fully understood. Finally, a low activity of the ATGL also results in storage
of fatty acyl-CoAs in the form of TAGs, thereby contributing to the detoxification
of hepatic lipids. This process can also be accelerated by hepatic oxidation of fatty
acyl-CoAs involving the transcription factors PPAR-α and -δ. In addition, the AMP-activated
kinase (AMPK) is involved. The adipokine adiponectin stimulates FA oxidation via AMPK
activation and PPAR-α induction. AMPK is also involved in the suppression of lipogenesis.
When these mechanisms of detoxification are overwhelmed or not active, lipotoxicity
prevails resulting in hepatic inflammation and insulin resistance. Via dysregulation
of secreted hepatokines (e.g., fetuin-A, SHBG, selenoprotein P), increased glucose
production and dyslipidemia, fatty liver then also induces systemic subclinical inflammation,
whole-body insulin resistance, hyperglycemia, and ultimately the manifestation of
type 2 diabetes and cardiovascular disease.