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Fatty Acid and Glucose Sensors in Hepatic Lipid
Metabolism: Implications in NAFLD
Michele Vacca, MD, PhD1,2 Michael Allison, MD, PhD3
Antonio Vidal-Puig, MD, PhD2
1 Medical Research Council - Human Nutrition Research (MRC-HNR),
Cambridge, United Kingdom
2 Department of Clinical Biochemistry and University of Cambridge
Metabolic Research Laboratories, Institute of Metabolic Science,
Cambridge, United Kingdom
3 Liver Unit, Department of Medicine, Cambridge Biomedical Research
Centre, Cambridge University NHS Foundation Trust, United
Kingdom
4 Department of Biochemistry, University of Cambridge, United
Kingdom
Julian L. Griffin, PhD1,4
Address for correspondence Antonio Vidal-Puig, MD, PhD, FRCP,
FmedSci, TVPLab, Metabolic Research Laboratories Level 4, Institute of
Metabolic Science, Box 289, Addenbrooke’s Hospital, Cambridge CB2
0QQ, United Kingdom (e-mail: [email protected]).
Michele Vacca, MD, PhD, Medical Research Council – Human Nutrition
Research (MRC-HNR) & Institute of Metabolic Science, University of
Cambridge, Elsie Widdowson Laboratory, 120 Fulbourn Road,
Cambridge CB1 9NL, United Kingdom
(e-mail: [email protected]).
Semin Liver Dis 2015;35:250–261.
Abstract
Keywords
► insulin resistance
► mitochondrial
dysfunction
► peroxisome
proliferator-activated
receptors
► sterol regulatory
element binding
protein 1
► carbohydrate
response elementbinding protein
The term nonalcoholic fatty liver disease (NAFLD) covers a pathologic spectrum from
lipid accumulation alone (simple steatosis) to steatosis with associated inflammation
and fibrosis (nonalcoholic steatohepatitis [NASH]). Nonalcoholic steatohepatitis can
progress to cirrhosis and potentially to hepatocellular carcinoma. Although a genetic
predisposition has been highlighted, NAFLD is strongly associated with an unhealthy
lifestyle and hypercaloric diet in the context of obesity and metabolic disease. The
dysregulation of specific pathways (insulin signaling, mitochondrial function, fatty acid,
and lipoprotein metabolism) have been linked to steatosis, but elucidating the
molecular events determining evolution of the disease still requires further research
before it can be translated into specific personalized interventional strategies. In this
review, the authors focus on the early events of the pathophysiology of NASH, dissecting
the metabolic and nutritional pathways involving fatty acids and glucose sensors that
can modulate lipid accumulation in the liver, but also condition the progression to
cirrhosis and hepatocellular carcinoma.
The liver is a key player in the modulation of whole body
energy homeostasis, and hepatic dysfunction is usually associated with systemic metabolic unbalances and vice versa.
The nonalcoholic fatty liver disease (NAFLD) spectrum includes histologic changes ranging from simple steatosis to
steatohepatitis (NASH), fibrosis, and cirrhosis (developing
in 29% of NASH patients) ultimately leading (in 27% of
NASH-cirrhosis patients) to hepatocellular carcinoma (HCC)
development.1–3 Steatosis is defined as an intrahepatic triglyceride (TG) deposition exceeding the 95th percentile of TG
content (> 55 mg/g of liver) for lean healthy individuals, or as
the presence of micro- or macrovesicles in > 5% of hepato-
Issue Theme Nonalcoholic Fatty Liver
Disease; Guest Editors, Christopher P.
Day, FMedSci, and Quentin M. Anstee,
BSc, MBBS, PhD, MRCP(UK)
cytes.2,3 Often benign and self-limited, steatosis can progress
when hepatocyte injury (ballooning and cell death), inflammatory infiltrates and/or extracellular matrix deposition
develop, histologic changes diagnosed as nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis has
emerged as the most rapidly increasing cause of chronic liver
disease; it is related to the epidemic of obesity extending to
both adults and children.4 Epidemiologic data has shown that
NAFLD is the typical hepatic manifestation of metabolic
syndrome (MetS), with a 50% prevalence of NAFLD in subjects
with diabetes, 76% in those with obesity, and 100% in those
morbidly obese with type 2 diabetes.3 Conversely, 50 to 100%
Copyright © 2015 by Thieme Medical
Publishers, Inc., 333 Seventh Avenue,
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Tel: +1(212) 584-4662.
DOI http://dx.doi.org/
10.1055/s-0035-1562945.
ISSN 0272-8087.
Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
of subjects with NASH are overweight, 50 to 60% have
systemic hypertension, and 50 to 60% have dyslipidemia.3
When compared with the general population, NAFLD patients
also show an increased mortality and risk for cardiovascular
disease (CVD).1
The first step in the pathophysiology of NAFLD is the
accumulation of lipids in the liver that follow an imbalance
between lipid acquisition and removal. Whether steatosis can
progress toward NASH, or these entities represent two different diseases, is still highly debated. In fact, it can be argued
that when lipids are qualitatively inert, they lead to “simple
steatosis.” Alternatively, when they are reactive, they promote
lipotoxicity and NASH due to the formation of TG-derived
toxic metabolites (e.g., diacylglycerols, ceramides, cholesterol, reactive oxygen species) ultimately causing hepatocyte
dysfunction, lipoapoptosis, and the development of proinflammatory and fibrogenic stimuli.2 Sources of increased
lipid (TG) in the liver include excess dietary TG intake,
enhanced intrahepatic TG synthesis (fatty acids formed
from de novo lipogenesis [DNL]), excess fatty acid (FA) influx
into the liver from adipose tissue lipolysis, diminished export
of lipids from the liver, and reduced fatty acid oxidation (FAO).
Nonalcoholic fatty liver disease thus results from excessive
storage of lipid species occasionally exceeding the capability
of the hepatocytes to accommodate them physiologically.5 All
these biochemical events are under the control of a complex
system of signaling/transcriptional pathways, governed by
hormones, cytokines, adipokines, and nutrient-sensing transcription factors. In this review, we will focus on the events
that coordinately induce lipotoxicity, namely: (1) adipose
tissue dysfunction, lipotoxicity, and insulin resistance; (2)
reduced oxidative potential of the liver; (3) unbalances in
lipoprotein trafficking; (4) prolonged positive energy balance
(►Fig. 1); and on how they are controlled by insulin and
nutrient-sensing transcription factors.
Adipose Tissue Dysfunction, Lipotoxicity,
and Insulin-Resistance
Patients with NAFLD typically present with hyperinsulinemia
and insulin resistance (IR). Insulin resistance originates from
the convergence of genetic predisposition and environmental
stressor factors, and has strong negative effects in liver
metabolism.2,6 In the liver, insulin is essential to control
the “fast-to-fed” metabolic shift in hepatic carbohydrate
metabolism (promoting hepatic glucose uptake, glycolysis,
and glycogen synthesis; inhibiting gluconeogenesis and glycogen utilization), and to modulate lipid metabolism (inhibiting FAO; promoteing DNL, free fatty acid [FFA] influx, and
very low-density lipoprotein [VLDL] secretion) thus leading
to hepatic lipid accumulation and to the promotion of hepatic
triglyceride export (inducing hypertriglyceridemia6,7). Under
physiologic conditions, insulin also inhibits lipolysis and FFA
release from adipose tissue (AT) repressing the activity of
hormone-sensitive lipase (HSL) (►Fig. 2).6,7 As a consequence
of hyperinsulinemia (with/without hyperglycemia) excess
glucose in the liver is converted to glycogen or is used to
produce acetyl-CoA (via glycolysis) to be either further
Vacca et al.
Fig. 1 Nutrient fate in relationship to caloric intake. During isocaloric
balanced feeding, nutrients are mainly used to produce energy and for
structural purposes (e.g., membranes, proteins, organelles, DNA).
Only a small quantity of these nutrients is stored during the fed states
(to be released during fasting). A continuous hypercaloric feeding is
associated with the need of storing excess calories. Cells have limited
carbohydrate-storage capacity as glycogen; as a consequence, proteins and carbohydrates are converted into fatty acids and triglycerides having neither osmotic nor colloidal effects for the cell, and
providing high caloric density (9 kcal/g).TGs, triglycerides.
metabolized or, alternatively, utilized as a substrate for
DNL.6,7 De novo lipogenesis facilitates the synthesis of saturated fatty acids (SFAs) for TG formation7 that can be stored
within hepatocytes or, alternatively, packaged into VLDL
lipoproteins to be secreted into the circulation (to be subsequently used in peripheral organs or stored in adipocytes).2
Triglycerides provide high caloric density (9 kcal/g), are
insoluble in water, and have neither osmotic nor colloidal
effects for the cell2; thus DNL is the preferred mechanism to
stock excess energy within the body. When DNL is overactivated in the liver because of hyperinsulinemia, it promotes hepatic fat accumulation leading to NAFLD, and
hypertriglyceridemia. Adipose tissue function is thus an
important factor in the pathophysiology of NAFLD and its
progression toward NASH as shown by the fact that loss of
function of key genes in adipogenesis promotes steatosis and
the progression of liver damage,8–10 and variants in genes
known to be associated to steatosis (e.g., PNPLA3) also affect
AT distribution.11 In health, AT protects the body from an
excessive exposure to fatty acids; when adipocyte expandability is exhausted, this event is associated with lipotoxicity
(the accumulation of toxic fatty acids derivatives in organs
different from AT) and peripheral insulin resistance. Adipose
tissue acquires a proinflammatory profile (suppression of
adiponectin, promotion of adipocytokines) and these events
in the liver lead to accumulation of lipid toxic species, reactive
oxygen species (ROS) production, endoplasmic reticulum
stress, activation of stellate cells, and progression of liver
damage.12,13 Adipose tissue dysfunction and IR are early
processes in the development of hepatic damage: In a population of “healthy” (nonobese, nondiabetic, normolipidemic)
biopsy-proven NAFLD patients, hyperinsulinemia, and
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Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
Vacca et al.
Fig. 2 Role of hepatic fatty acid metabolism in the development of hepatic steatosis. Hepatic lipid accumulation can result from (1) a prolonged positive
energy balance, (2) adipose tissue dysfunction and insulin resistance, (3) impairment of fatty acid oxidation and mitochondrial function, and (4) unbalances
in lipoprotein trafficking. Insulin-mediated activation of SREBP1 proteins and glucose-mediated activation of ChREBP play a major role in these processes.
Continuous arrows represent direct biochemical reactions, dash arrows represent modulatory mechanisms. ApoEr, ApoE receptor; FAT/CD36, fatty acid
translocase/cluster differentiation protein-36; CETP, cholesteryl ester transfer protein; ChREBP, carbohydrate response element-binding protein; CM,
chylomicrons; HDL, high-density lipoprotein; HSL, hormone-sensitive lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLr, lowdensity lipoprotein receptor; OxLDL, oxidized low-density lipoprotein; Ox-Phos, oxidative phosphorylation; sLDL, small low-density lipoprotein; SREBPs, sterol
regulatory element binding proteins; TG, triglyceride; VLDL, very low-density lipoprotein.
AT/hepatic IR already coexist at the time of the diagnosis and
progressively increase across NAFLD stages; of note, AT IR
independently predicts liver histology and alters cardiometabolic risk parameters.14 Conversely, NAFLD can occur also in
the absence of peripheral IR.3,5 Rats fed with a short-term
high fat diet (HFD) develop hepatic fat accumulation and
hepatic IR in the absence of changes in the whole body IR.15
Even if it is still debated whether peripheral or hepatic IR
arises first, adipocyte dysfunction represents a contributing
factor to the onset of lipotoxicity and (both peripheral and
hepatic) IR, and could have a major role for the progression of
fatty liver disease.
Fatty Acid Oxidation, Mitochondrial
Function, and the Progression of NASH
Fatty acid β-oxidation allows the oxidation of FAs into acetylCoA, a substrate for oxidative phosphorylation (OXPHOS),
ketone body formation, or for other biochemical reactions
(e.g., gluconeogenesis or DNL).16,17 In normal conditions,
β-oxidation occurs in mitochondria more than in peroxisomes. Mitochondrial β-oxidation is mostly controlled by
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the uptake of FA into the mitochondrial matrix via carnitine-palmityl-transferase 1 (CPT-1), which is inhibited by
malonyl-CoA.16,17 Fatty acids can be metabolized exclusively
in the presence of oxygen as the final acceptor of the reducing
equivalents deriving from their oxidation by the four mitochondrial respiratory complexes. The mitochondrial respiratory complex couples the electron transfer activities to Hþtranslocation from the matrix to the outer side of the mitochondrial inner membrane thus building up a transmembrane electrochemical potential (Δψ).16,17 When adenosine
diphosphate (ADP) is available, this electrochemical gradient
is utilized for adenosine triphosphate (ATP) synthesis by ATP
synthase, or it can otherwise exert a negative control feedback on the respiratory flux.16,17 Furthermore, ROS overproduction occurs when mitochondrial FAO supplies excessive
respiratory substrates in the absence of a concomitant upregulation of mitochondrial respiratory chain activity, increases
mitochondrial membrane potential (Δψ), or produces imbalances in the ATP/ADP ratio causing stalling of the respiratory
flux.16,17 Excess FAs and ROS also promote uncoupling proteins (UCPs) activation that lower the mitochondrial Δψ and
the intracellular oxygen tension increasing the respiration
Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
rate (thus leading to reduced ROS production); this is a relay
system that, when overactivated (e.g., in obesity and steatosis), affects OXPHOS efficiency.16 Thus, FAO itself promotes
the saturation of the oxidative system in steatosis, and leads
to mitochondrial dysfunction and to the promotion of the
extramitochondrial (microsomal and peroxisomal oxidation)
oxidation systems.16–18 Ω-oxidation of FAs is normally a
minor pathway of FAO because one of its key enzymes,
cytochrome P450 4A (CYP4A), is inhibited by insulin. Hence,
IR leads to a significant overactivation of this pathway that
produces long-chain dicarboxylic acids that further inhibit
mitochondrial function.16–18 Long-chain dicarboxylic acids
(and very long chain FAs) can be metabolized by the peroxisomal β-oxidation to complete their oxidation processes in
mitochondria; the genetic ablation of enzymes involved in
the peroxisomal β-oxidation leads to hepatic steatosis.19
Mitochondrial dysfunction and the activation of the extramitochondrial oxidation systems are thus key events in the
development of a lethal vicious cycle able to generate a
dramatic amplification of ROS production and liver damage
that promotes the progression of NAFLD into NASH. The
mitochondria are also the primary targets ROS-induced damage: Oxidative modifications of the respiratory complexes are
associated with the impairment of their catalytic functions,
mutagenesis of the mitochondrial DNA, mitochondrial dysfunction, and propagation of the oxidative damage, thus
leading to hepatocellular death and NASH progression.17
Strategies aimed to improve the cellular REDOX homeostasis
by supplying the hepatocyte with nonenzymatic antioxidant
molecules (such as vitamin E20) could thus be a promising
approach to the management of NASH.
If Lipoproteins Deal with Liver’s Fat, What
Goes Wrong in Steatosis?
The liver is the major regulator of metabolite flux in the body,
processing lipids provided by diet and AT-released FFAs
(contributing in equal amounts), and to a smaller part by
DNL in the liver itself. During the development of IR, the
massive increase of FFA and the promotion of DNL render
lipoprotein trafficking efficiency a critical step in the pathophysiology of NAFLD.2,21 The fate of newly formed or dietary
lipids is to be oxidized, or to be esterified to TGs, incorporated
into VLDL, secreted into the systemic circulation and delivered to the peripheral tissues. Very low-density lipoprotein
particles are constituted by apolipoprotein (Apo) B-100
(ApoB-100) and C (ApoC), lipids (TGs and cholesterol esters),
and phospholipids. Within the hepatocytes, microsomal
transfer protein (MTP) promotes ApoB-100 fusion with TGs
droplets, and VLDL formation and secretion.2,21 In the initial
phases of steatosis, lipid accumulation is counterbalanced by
increased VLDL secretion, but this adaptive mechanism
reaches a point at which it is inadequate to compensate for
the degree of intracellular TG accumulation.22,23 In fact, the
VLDL-ApoB-100 secretion rates (the rate-limiting step in
VLDL formation) is not increased in subjects with steatosis,
thus leading to the production of very large TG-rich VLDL
(that cannot be secreted through the sinusoidal endothelial
Vacca et al.
pores) and impairment of VLDL synthesis and export.24
Subsequently, serum levels of LDL and of the atherogenic
small LDL (sLDL) also increase due to the promotion of
cholesteryl ester transfer protein (CETP; enriches VLDL in
cholesterol), and of hepatic lipase ([HL] regulates plasma
concentration of the atherogenic lipoproteins intermediatedensity lipoproteins -IDL- and of sLDL). Both CETP and HL
activities are increased in NAFLD and may favor the formation
of sLDL.2
Dietary lipids are absorbed by enterocytes, incorporated in
TG-rich chylomicrons, transported into the systemic circulation, and then delivered to the liver (20%) or peripheral tissue
(80%), where lipoprotein lipase ([LPL] the rate-limiting step of
TG uptake) releases FFAs for uptake.2 One of the strongest
inhibitors of LPL is apolipoprotein C-III (ApoC-III; an essential
constituent of VLDL particles), and a loss of function of this
apolipoprotein has been associated with obesity and metabolic complications due to an enhanced peripheral activity of
LPL.25 On the other hand, the overexpression of ApoC-III
promotes liver steatosis and hepatic insulin resistance due
to reduced peripheral FFA uptake, increased hepatic triglyceride delivery, and surprisingly, a reduction in hepatic triglyceride secretion.26 Interestingly, insulin and glucose exert
opposite effects on ApoC-III, which is promoted by glucose
and inhibited by insulin27,28; insulin instead promotes the
expression of transporter fatty acid translocase / cluster
differentiation protein-36 (FAT/CD36 mediates the uptake
and the intracellular transport of FAs), thus facilitating lipid
accumulation in the liver.29 In individuals with IR, insulin fails
to suppress efficiently ApoC-III in the liver (thus leading to LPL
inhibition in peripheral tissues, and to the increase of the
hepatic uptake of TGs-rich chylomicrons remnants) and
hormone-sensitive lipase (HSL) in AT (thus leading to an
increase of adipose-derived FFA flux to the liver).29,30 Hepatic
IR thus promotes a progressive deterioration of steatosis and a
deleterious lipoprotein profile; this is the strongest evidence
linking hepatic steatosis to the consequences of obesity and
metabolic syndrome.
Diet, Nutrient Sensors, and Modulation of
Lipid Metabolism
Sugar or Fat: Which Is the Enemy?
Insights for addressing the role of excess calories and diet
composition in the pathophysiology of NAFLD come from the
study of animal models fed high-energy diets. Although not
standardized in macronutrient content or composition, these
studies show that prolonged energy excess, especially in the
form of high carbohydrate or fat, rapidly induces fatty liver
with differences in the progression of liver injury potentially
depending on macronutrient composition.31,32 When energy
balance is positive, mammalian livers preferentially use glycolysis to generate energy, while excess glucose is stored in
the form of glycogen (glycogen synthesis) and fatty acids
(DNL) that will be stored in the adipose tissue in the form of
triglycerides; when positive excess energy intake is prolonged, the liver is also able to store significant quantities
of lipids leading to hepatic steatosis (►Fig. 1).31,32 In terms of
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Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
macronutrient composition, high sucrose/fructose diets induce intrahepatic lipid accumulation independently from
their fat content, and do not necessarily progress toward
steatohepatitis.32–34 On the other hand, it has also been
shown that “high-fat” diets (35–70% of total calories constituted by fat) induce steatosis and liver damage not only due to
fat content, but also due to their content in simple sugars. For
example, ketogenic diets (very high in fat with almost no
carbohydrate) neither induce massive steatosis nor raise
alanine aminotransferase (ALT) outside the normal range.35
Saturated fat is able to stimulate both FAO via a peroxisome
proliferator activated receptor-α (PPAR-α) dependent mechanism and DNL in the liver, but the prominence of these
effects seems to depend on sucrose content;36,37 when
saturated fat is consumed without sucrose, FAO promotion
is the prominent feature, thus leading to minimal hepatic
steatosis or liver injury.37 Diets that incorporate both macronutrients (carbohydrate and fat) thus appear to represent a
situation closer to the so-called “Western” diet; such diets
(enriched in saturated fat, cholesterol, sucrose and/or fructose) induce obesity, insulin resistance, and hepatic steatosis,
along with different degrees of hepatic injury, inflammation,
and mild fibrosis.38–40 The types of FA have also been invoked
as a factor contributing to differences in the capability of diets
to induce steatosis, for example, both small/medium-chain
FAs (that need more energy to be utilized) and long-chain
saturated FAs alone (stimulating FAO by promoting PPARα
and its coactivator PGC-1-α) fail to induce massive steatosis,36,37,41 whereas transfats (> 15% of total calories)42,43
promote hepatic steatosis even in the absence of free sucrose.
The role of polyunsaturated fatty acids (PUFAs) is still discussed because they decrease liver triglyceride content and
plasma ALT levels in leptin-deficient mice,44 but when administered in excess (> 35% of total calories) via total enteral
nutrition, PUFAs overfeeding causes steatosis and liver
damage.45
Therefore, micronutrient composition could affect the
capability of a specific diet to induce DNL and/or FAO. Further
studies are necessary to assess whether specific nutrient
mixtures cause liver injury in excess to their ability to induce
hepatic steatosis.
Sterol Regulatory Element Binding Protein 1c and
Carbohydrate-Response Element-Binding Protein:
Partners in DNL Promotion
De novo lipogenesis is finely regulated at the transcriptional
level mainly by two transcription factors, the sterol regulatory element binding protein 1 (SREBP1), and the glucose
sensor carbohydrate response element-binding protein
(ChREBP), which are activated by insulin and glucose, respectively. Both these transcription factors promote the expression of key enzymes for DNL (e.g., ATP citrate lyase [ACL];
acetyl-CoA carboxylase [ACC]; fatty acid synthase [FAS]).7,46
Insulin, SFAs, and the oxysterol sensor liver X receptor
(LXR) promote SREBP1c,47,48 whereas PUFAs, glucagon, and 5'
AMP-activated protein kinase (AMPK) signaling inhibit
it.44,48,49 The relationship between insulin and SREBP-1c is
finely regulated: Insulin promotes the expression of a SREBPSeminars in Liver Disease
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Vacca et al.
1-mediated negative loop that activates DNL, but limits an
excessive activation of this metabolic pathway toward the
promotion of SREBP-1c inhibitor insulin-induced gene 1
(Insig1)50,51; SREBP-1c also negatively feedbacks insulin signaling through the inhibition of insulin receptor substrate 2
(IRS2), thus silencing phosphatidylinositol 3-kinases/protein
kinase B, PI3K/Akt cascade.52,53 In obesity, hyperinsulinemia
thus boosts SREBP-1c activation, which promotes DNL, negatively feedbacks insulin signaling (leading to decreased glycogen synthesis and increased gluconeogenesis), and directly
promotes gluconeogenesis (e.g., phosphoenolpyruvate
carboxykinase [PEPCK]), thus inducing steatosis and
hyperglycemia.7,52
Increased intracellular glucose levels activate ChREBP54
resulting in the induction of the transcription of genes
involved in glycolysis (e.g., liver pyruvate kinase [LPK]) and
DNL,55 causing a further worsening of steatosis.5 In murine
models of obesity, liver-specific adenovirus-mediated inhibition of ChREBP markedly impairs lipogenic gene expression in
the liver, protects from hepatic steatosis, ameliorates insulin
signaling and overall glucose tolerance, and also decreases
plasma levels of triglycerides and nonesterified fatty acids.56
In patients with NASH, ChREBP expression correlates with the
degree of steatosis; however, its expression decreases in the
presence of severe insulin resistance.57 ChREBP overexpression promotes DNL genes and stearoyl-CoA desaturase-1
(Scd1), a critical regulator of energy metabolism that catalyzes the transformation of SFAs into monounsaturated fatty
acids (MUFAs). As a consequence, ChREBP activation results in
a prevalent accumulation of MUFAs that does not impact
much on insulin sensitivity.57 In this the concomitant knockdown of Scd1 worsens insulin sensitivity.57 These findings are
in line with a previous report showing that liver-specific Scd1
knockout (KO) mice are protected from steatosis when fed a
high-carbohydrate very low-fat diet.32
Therefore, SREBP1c and ChREBP activation in hyperinsulinemic subjects has a crucial role in the development of
hepatic lipid accumulation (►Fig. 2). The relative balance
between SREBP1c and ChREBP contribution in modulating
the lipogenic pathway could have different outcomes for the
accumulation of specific lipid species and for the degree of IR,
and could potentially explain different outcomes in terms of
MetS complications.58,59
Peroxisome Proliferator-Activated Receptors and Their
Coactivators in the Modulation of Hepatic Lipid
Accumulation
Lipid-sensing nuclear receptors (NRs) are transcription factors participating in the control of complex processes in living
organisms. Nuclear receptors show considerable specificity in
their activation and tissue-specific expression.60 In the human genome, 48 NRs have been identified, while in rodents
there are 49.61 A subfamily of these transcription factors,
known as “adopted-orphan NRs” acts as lipid sensors and
have been involved in the pathophysiology of MetS.62 Of
particular interest for the pathophysiology of NAFLD, are
the “fatty acid sensors” peroxisome proliferator-activated
receptors (PPARs) and their coactivators peroxisome
Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
proliferator-activated receptor γ coactivators 1 (PGC1s;
see ►Table 1). Peroxisome proliferator-activated receptors
(PPARα/NR1C1; PPARβ/δ/NR1C2; PPARγ/NR1C3) form heterodimers with the retinoid X receptors (RXR) to control
metabolic programs and to regulate energy homeostasis.62
Peroxisome proliferator-activated receptors bind to specific
DNA consensus sites termed PPAR response elements
(PPREs). Although sharing sequence and structure homology,
PPARs are characterized by specific ligand-binding domains
(that can accommodate a wide diversity of natural and
synthetic compounds), tissue distributions, and physiologic
functions.63
Peroxisome Proliferator-Activated Receptor α
Peroxisome proliferator-activated receptor α (PPARα) is
prominently expressed in the liver (also expressed at a lower
level in kidney, heart, skeletal muscle, small intestine, brown
AT, and immune cells) and can be activated by fatty acids, 1palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine, fibrates,
highly selective PPARα agonists (e.g., LY518674), and
SPPARMs (selective PPAR modulators).63 The major physiologic function of PPARα is to promote fatty acid utilization
during fasting to allow gluconeogenesis,44,64,65 but PPARα is
also one of the key regulators of the response to excess fat. In
fact, PPARα modulates fatty acid uptake (fatty acid binding
protein [FATP], CD36, CPT-1) and lipid trafficking (promotion
of LPL and apoA proteins; inhibition of the LPL inhibitor
apoCIII and of proprotein convertase subtilisin/type 9
[PCSK9]), promotes β-oxidation (acyl-CoA oxidase [ACOX],
thiolase, acyl-CoA-dehydrogenase, cytochrome P450-ω-hydroxylase), and inhibits DNL.64,66–69 Given the ability of
PPARα agonists to modulate both TG and HDL metabolism,70,71 fibrates are thus employed for the management
of primary hypertriglyceridemia and mixed hyperlipid-
Vacca et al.
emia.72,73 Peroxisome proliferator-activated receptor α has
also shown a potential in the regulation of the pathophysiologic events causing liver steatosis. Following a high-fat diet
(HFD), high fructose or methionine-choline deficient ([MCD];
a model to induce NASH) diets, PPARα null mice develop
hypertriglyceridemia and are more susceptible to steatosis
and to the progression of NASH due to an impairment of
mitochondrial fatty acid β-oxidation, and to increased hepatic
oxidative stress and expression of proinflammatory genes.
These mice also develop massive steatosis, lobular inflammation, with a significant increase of the NASH activity score
when compared with wild-type animals.74–76 Conversely,
PPARα ligands protect the liver from NAFLD and NASH,
promoting fatty acid oxidation, and reducing endoplasmic
reticulum stress, hepatic insulin resistance, glucose intolerance, and levels of expression of inflammatory genes.74,77–79
Despite the robustness of this evidence in animal models,
only few trials with relatively low numbers of patients have
been performed to confirm these results in humans, and have
not so far provided additional support for significant efficacy
in NASH. Although clofibrate was not effective in the management of NASH,80 fenofibrate was able to ameliorate the
degree of metabolic impairment (especially fasting glucose,
triglycerides, and apolipoprotein A1), and improve liver
enzymes in a small cohort of patients with NASH; however,
its effects on liver histology were minimal.81
Peroxisome Proliferator-Activated Receptor β/δ
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ)
exhibits a broad expression pattern63,82 and can be activated
by polyunsaturated fatty acids (eicosapentaenoic acid [EPA],
arachidonic acid [ARA], and dihomo-γ-linoleic acid), prostaglandins (PGs; PGA1, PGE2, PGD2, prostacyclin -PGI- and its
stable analogue carba-prostacyclin), 4-hydroxynonenal, and
Table 1 Potential relevance of peroxisome proliferator-activated receptor (PPARs) and peroxisome proliferator-activated receptor γ
coactivators (PGCs) in the pathophysiology of nonalcoholic fatty liver disease
PPARα
PPARβ/δ
De novo lipogenesis
↓
?
Fatty acid oxidation & mitochondrial function
"
"
Fatty acids uptake
"
/
Lipoprotein transport
"
"
Gluconeogenesis
"
Glycolysis
PPARγ
PGC1α
PGC1β
/
"
"
"
"
"
"
/
"
"
"
/
" (hepatic)
↓ (AT/systemic)
"
/
"
"
"
"
"
"
Inflammation/damage
↓
↓
↓
↓
↓
Steatosis
↓
?
" (hepatic)
↓ (AT/systemic)
↓
↓
Hepatic insulin sensitivity
"
"
↓ (hepatic)
" (AT/systemic)
"
¼
Triglycerides
↓
↓
" (hepatic)
↓ (AT/systemic)
↓
"
Abbreviations: ?, contradictory results; /, not investigated; ", promoted; ↓, inhibited; ¼, unchanged; hepatic, effects of hepatic-specific modulation;
AT/systemic, effects of systemic or adipose tissue-specific modulation.
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Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
selective synthetic agonists (GW501516, GW0742).83–85 In
the liver, PPARβ/δ controls fatty acid oxidation and the
uncoupling of oxidative phosphorylation through activation
of its target genes such as long chain acyl-CoA dehydrogenase
(LCAD), CPT-1, ACOX1, long chain acyl-CoA-synthetase (ACSL)
and UCP-1. Depending on the organ targeted and the experimental design used, PPARβ/δ has shown positive or negative
action on liver steatosis, but an overall beneficial action on its
progression. Adipose tissue-specific overexpression of
PPARβ/δ in rodents protects from diet-induced obesity, hypertriglyceridemia, and hepatic steatosis.86 In models of
obesity-induced steatosis (HFD and ob/ob), pharmacologic
or liver-specific adenoviral activation of PPARβ/δ promotes
hepatic fatty acid oxidation (increase of plasma β-hydroxybutyrate and of mRNA expression of PPARα and its target
genes, promotion of the AMPK/PGC-1α-lipin1/PPARα pathway) and the Krebs cycle,87,88 but also stimulates (AMPKmediated) insulin sensitivity, thus reducing fasting glucose
levels, promoting hepatic glycogen deposition, and glycolysis.87,89 The effects of PPARβ/δ activation on DNL are controversial because some authors show that PPARβ/δ directly
promotes the transcription of Insig-1 (thus leading to
SREBP1c inhibition, DNL suppression, and reduced hepatic
steatosis in obese diabetic db/db mice), whereas other authors indicate that PPARβ/δ induces hepatic lipid production
mainly in the form of unsaturated (rather than saturated)
fat.89,90 In both cases, liver damage has been shown to be
reduced,89,90 and this goes in line with the inhibitory effect of
PPARβ/δ on STAT3 phosphorylation that prevents the activation of proinflammatory signals (e.g., tumor growth factor β1,
interleukin- [IL-] 6, IL-1β, MCP-1, tumor necrosis factor α,
nuclear factor-κB1).91,92 Animal and human studies also
provide evidence that PPARβ/δ is beneficial on lipoprotein
metabolism because PPARβ/δ activation increases apoAI,
apoAII, and HDL-cholesterol, while reducing small dense
LDL levels.93–97 Apparent discrepancies in the role of
PPARβ/δ to modulate DNL could be thus explained by the
different experimental designs (i.e., obesity models, PPARβ/δ
activation strategies) that preferentially select for specific
functions of PPARβ/δ, depending on the pathophysiologic
context. It seems likely that in the liver PPARβ/δ physiologically reacts to an excessive accumulation of lipids and/or
products of oxidative stress and/or proinflammatory mediators (prostaglandins) to limit further accumulation of fat (by
promoting FAO), to prevent hepatic insulin resistance (by
promoting AMPK/PGC1α axis), and to limit further FA production associated with an excessive diet-induced insulinmediated activation of DNL (by promoting Insig-1). Nevertheless, analysis of the PPARβ/δ function in the progression of
NASH deserves further attention because it has been shown
that it promotes stellate cell activation and fibrosis (upon
CCL4 challenge),98 and its role in hepatic proliferation and
hepatocarcinogenesis is contentious.99,100
Peroxisome Proliferator-Activated Receptor γ
The PPARγ gene encodes for three splicing variants giving rise
to two functional proteins (PPARγ1 and PPARγ3 transcripts
encode for PPARγ1 and is expressed in AT, immune cells,
Seminars in Liver Disease
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Vacca et al.
intestine, liver, and kidney; PPARγ2 transcript encodes for a
protein expressed in ATs). Peroxisome proliferator-activated
receptor γ is an important transcriptional regulator of adipocyte differentiation and function.9,10,63 Mutations in the
PPARγ gene (e.g., familial partial lipodystrophy type 3
[FPLD3], PPARγ Pro12Ala, C1431T polymorphisms) induce
severe insulin resistance, dyslipidemia, steatosis, and earlyonset hypertension.101–105 A wide spectrum of PPARγ ligands
has been identified, ranging from the potential natural
ligands including monounsaturated and polyunsaturated
FA, eicosanoid FA-derivatives (hydroxyoctadecanoic acid
[HODE]; 13-HODE and 9-HODE), and prostanoids (e.g.,
15-deoxy-Δ12,14-prostaglandin J2) to the pharmacologic agonists thiazolidinediones (TZDs), selective PPARγ modulators
(SPARMs), partial PPARγ/α agonists (e.g., TDZ18), curcumin,
protopanaxatriol, and harmine.72,106 Thiazolidinediones
(pioglitazone and rosiglitazone) have been approved for
clinical use in type 2 diabetes, and proposed as possibly
effective in NASH.107 The primary therapeutic effect of
TZDs is to promote the expansion of subcutaneous AT due
to an enhanced differentiation of preadipocytes in mature
adipocytes. This event promotes lipid repartitioning from
visceral fat, liver, and skeletal muscle to the subcutaneous AT,
preventing lipotoxicity-induced insulin resistance and increased circulating levels of FFA.8,9,108 Peroxisome proliferator-activated receptor γ also stimulates adiponectin
secretion (by promoting AMPK signaling and FA oxidation,
while inhibiting hepatic gluconeogenesis)63,109 and is a negative modulator of the proinflammatory cascades in the liver
thus potentially preventing the progression of NASH.110
Tissue-specific PPARγ modulation strategies have provided
the evidence that PPARγ exerts its beneficial effects on liver
steatosis mainly due to its action in AT.8,10,111–115 A targeted
deletion of PPARγ in AT is associated with elevated plasma
levels of FFAs and triglycerides and increased susceptibility to
HFD-induced steatosis, hyperinsulinemia, and IR.8 On the
other hand, hepatocyte-specific PPARγ-knockout mice are
protected against HFD-induced hepatic steatosis, show improved glucose tolerance, and reduced gluconeogenesis. Peroxisome proliferator-activated receptor γ-knockout mice are
also characterized by a downregulation of genes involved in
lipogenesis (SCD1, SREBP-1c, and ACC), lipid transport (CD36/
FAT, L-FABP, and MTP), and β-oxidation (PPARα and ACO).115
As a confirmation of a candidate “pro-steatotic” action of
PPARγ into the liver, adenoviral PPARγ hepatic overexpression
causes hepatic steatosis,116 overexpression of genes involved
in fatty acid transport, and triglyceride synthesis.114,116
However, the pharmacologic systemic activation of PPARγ
using TZDs has been suggested to be potentially beneficial in
the management of NAFLD20 because the net result of systemic PPARγ activation is to (1) increase AT lipid uptake and
storage, (2) decrease serum FFA and TG, (3) increase peripheral glucose absorption, and (4) enhance energy expenditure.
Altogether these effects improve insulin sensitivity, and
reduce hepatic gluconeogenesis and steatosis.9,63 Unfortunately, although effective in controlling glycosylated hemoglobin and reducing liver steatosis, the enthusiasm for TZDs
as therapeutic agents has been limited in recent years
Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
because they are not devoid of side effects such as weight gain
(2–3 kg per 1% glycosylated hemoglobin lowered), anemia,
pulmonary edema, congestive cardiac failure, and increased
risk of myocardial infarction.117 Thus rosiglitazone was voluntarily withdrawn from the market despite being one of the
most effective drugs in reducing glycosylated hemoglobin.
Peroxisome Proliferator-Activated Receptor γ
Coactivators
A more radical approach to the treatment and the prevention
of NASH could be the modulation of lipid homeostasis by
strategies aiming at inducing peroxisome proliferator-activated receptor γ coactivator 1 (PGC1) α and β. First characterized as important regulators of mitochondrial biogenesis
and function, PGC1s have been described as central coordinators of metabolic homeostasis and their modulation appears to be potentially beneficial in NAFLD.
Peroxisome proliferator-activated receptor γ coactivator
1α coactivates multiple transcription factors (FoxO1, glucocorticoid receptor, hepatic nuclear factor-4α, estrogen-related receptor-α, and PPARα), thus acting as a key promoter of
gluconeogenesis, fatty acid oxidation, lipid transport, and
oxidative phosphorylation during times of nutrient deprivation.118 Hepatic PGC1α transcription is induced by fasting
(because it is promoted by glucagon and inhibited by insulin),
HFD, obesity, and insulin resistance. PGC1a is also tightly
modulated at posttranscriptional level (e.g., by the AMPK/
SIRT pathway that is activated by cold, exercise, metformin,
resveratrol, and other stimuli).118 PGC1α KO mice develop
metabolic abnormalities in energy-demanding organs that
lead to increased body fat, susceptibility to cold and, following short term starvation, hepatic steatosis (due to a combination of reduced mitochondrial respiratory capacity,
promotion of lipogenic genes, and increased supply of
FAs).119 Hepatic-specific PGC1α heterozygous mice show
hypertriglyceridemia (due to increased expression of genes
involved in triglyceride-rich lipoprotein assembly), hepatic
steatosis and diminished ketogenesis during fasting (decreased expression of genes involved in β-oxidation). These
mice also develop hepatic insulin resistance following HFD.120
Interestingly, mice lacking SIRT1 (one of the upstream regulators of the PGC1α/PPARα pair) in the liver show a similar
phenotype. When fed with HFD, SIRT1 KO mice develop
hepatic steatosis, hepatic inflammation, and endoplasmic
reticulum stress due to the suppression of PGC-1α/PPARα.121
Altogether, these data indicate that pharmacologic modulation
of AMPK/SIRT1 cascade could be an effective approach to
preventing obesity-associated metabolic diseases.
Peroxisome proliferator-activated receptor γ coactivator
1β is considered an important regulator of metabolism in the
liver because it coactivates different key transcription factors
(including estrogen-related receptors, nuclear respiratory
factor 1, liver X receptors, etc.) involved in mitochondrial
biogenesis, oxidative metabolism, lipogenesis, and TG secretion. HFD stimulates not only the expression of SREBP1 in
liver, but also of PGC1β, which contributes to the induction of
the lipogenic program facilitating the release of triglycerides
and cholesterol in VLDL particles. However, unlike SREBP1,
Vacca et al.
PGC1β reduces fat accumulation in the liver through concomitant stimulation of FAO and lipoprotein transport.122 The
global knockout of PGC1β, although not showing overt phenotype under normal laboratory conditions, is characterized
by a general defect in the expression of genes involved in the
electron transport chain of the mitochondria; and, in response to acute high fat dietary loads, the lack of PGC1β
impairs hepatic lipid metabolism in the liver, resulting in
hepatic steatosis123,124 and reduced lipoprotein-associated
triglyceride and cholesterol content.123 Conversely, MCD-fed
hepatocyte-selective PGC1β transgenic mice are protected
from lipid overload and from the progression to fibrosis due
to a coordinated promotion of mitochondrial function and
lipoprotein metabolism, and a reduction of oxidative
stress.125
In the context of liver steatosis, the selective modulation of
PGC1 proteins and their targeted pathways is thus a candidate
strategy to protect the liver from lipid accumulation and
oxidative damage due to the pleiotropic action of these
coactivators in lipid homeostasis. However, to date the strategies aiming at activating this pathway rely on indirectly
modulating PGCs upstream cascades (e.g., with metformin,
resveratrol, etc.) or on stimulating the relevant coactivated
receptor (e.g., PPARs), whereas mechanisms to target PGC1
proteins directly in humans are still being sorted.
Conclusion
Hepatic steatosis and NASH are the hepatic manifestation of
lipid-induced toxicity in the context of MetS, and are closely
related to excessive dietary calorie intake, obesity, and
impaired metabolic homeostasis. The close interrelationship
between obesity, AT dysfunction, onset of IR, and NAFLD have
been widely characterized, with defective insulin signaling,
impaired mitochondrial function, and dysregulated lipoprotein trafficking being the key effectors leading to hepatic TG
accumulation. However, the exact natural history of the
disease and the factors responsible for the progression
toward liver damage still remain elusive. Although lipotoxicity, oxidative stress, exogenous factors (e.g., drugs, microbiota, alcohol, and fructose consumption), and genetic
predisposition have been proposed as modulators in this
progression, more detailed insights are needed to elucidate
the mechanisms responsible for the evolution of NAFLD
toward more severe forms of hepatic disease. Currently,
the modulation of lifestyle through diet and exercise and
the management of obesity, insulin resistance, and diabetes
are the toolkit of management with proven positive effects
on steatosis likely to reduce the risk of progression of
established NASH. However, a more detailed characterization of the pathways that define lipid-related reactive toxic
species that cause the lipid-related hepatocyte cell death
inflammation as well as those attempting to promote regeneration, hepatic stellate cell activation, and extracellular
matrix deposition may provide an integrated picture of the
pathophysiology of NASH and identify novel therapeutic
approaches to prevent its progression toward cirrhosis and
HCC.
Seminars in Liver Disease
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258
Fatty Acid and Glucose Sensors in Hepatic Lipid Metabolism
Vacca et al.
Abbreviations
Acknowledgments
Prof. Vidal-Puig was funded by the MRC and BHF program
grants; Dr. Vacca and Dr. Griffin by MRC program grant
(MC_PC_13030); Dr. Allison by the Evelyn Trust Grant. Dr.
Vacca was a fellow of Fondazione Umberto Veronesi (Italy).
The authors are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union
under Grant Agreement 634413.
ACC
ACL
ACSL
ACOX
ADP
Apo
ARA
AT
ALT
ATP
ChREBP
CPT-1
CVD
CYP4A
DNL
EPA
FA
FAS
FATP
FFA
FAO
FPLD3
HCC
HFD
HL
HODE
HSL
Insig1
IR
IRS2
IL
LCAD
LPL
MetS
MTP
NAFLD
NASH
OXPHOS
PCSK9
PEPCK
PG
PGC1
PPARs
PPREs
PUFAs
ROS
RXRs
SPARMs
SREBP1
TG
TZDs
UCPs
VLDL
acetyl-CoA carboxylase
ATP citrate lyase
acyl-CoA-synthetase
acyl-CoA oxidase
adenosine diphosphate
apolipoprotein
arachidonic acid
adipose tissue
alanine aminotransferase
adenosine triphosphate
carbohydrate response element-binding protein
carnitine palmityl transferase 1
cardiovascular disease
cytochrome P450 4A
de novo lipogenesis
eicosapentaenoic acid
fatty acid
fatty acid synthase
fatty acid binding protein
free fatty acid
fatty acid oxidation
familial partial lipodystrophy type 3
hepatocellular carcinoma
high-fat diet
hepatic lipase
hydroxyoctadecanoic acid
hormone-sensitive lipase
insulin-induced gene 1
insulin resistance
insulin receptor substrate 2
interleukin
long chain acyl-CoA dehydrogenase
lipoprotein lipase
metabolic syndrome
microsomal transfer protein
nonalcoholic fatty liver disease
nonalcoholic steatohepatitis
oxidative phosphorylation
proprotein convertase subtilisin/type 9
phosphoenolpyruvate carboxykinase
prostaglandin
peroxisome proliferator-activated receptor γ
coactivator 1
peroxisome proliferator-activated receptors
PPAR response elements
polyunsaturated fatty acids
reactive oxygen species
retinoid X receptors
selective PPARγ modulators
sterol regulatory element binding protein 1
triglyceride
thiazolidinediones
uncoupling proteins
very-low-density lipoprotein
Seminars in Liver Disease
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No. 3/2015
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