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M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08

Available online at www.sciencedirect.com

Metabolism
www.metabolismjournal.com

Reviews

Non-alcoholic fatty liver disease: A sign of systemic


disease
Isabella Reccia, Jayant Kumar, Cherif Akladios, Francesco Virdis, Madhava Pai,
Nagy Habib, Duncan Spalding
Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK

A R T I C LE I N FO AB S T R A C T

Article history: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and
Received 18 February 2017 leading cause of cirrhosis in the United States and developed countries. NAFLD is closely
Accepted 23 April 2017 associated with obesity, insulin resistance and metabolic syndrome, significantly contrib-
uting to the exacerbation of the latter. Although NAFLD represents the hepatic component
Keywords: of metabolic syndrome, it can also be found in patients prior to their presentation with
Fatty liver other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely
NAFLD intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly
NASH involved in its pathogenesis and progression. In this review, we bring together the current
Insulin resistance understanding of the pathogenesis that makes NAFLD a systemic disease.
Obesity 2017 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2. Changes in Metabolism Contributing to NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2.1. Energy Intake and Diet Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Abbreviations: ACC, acetyl-CoA carboxylase; ApoB, apolipoprotein B; ApoCII, apolipoprotein C-II; APPL-1, adaptor protein containing
pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif; CD36, fatty acid translocase; CETP, cholesteryl
ester transfer protein; ChREBP, carbohydrate-responsive element-binding protein; CKD, chronic kidney disease; COX, cyclooxygenase;
CPT1, carnitine palmitoyltransferase 1; CVC, cardiovascular disease; DAG, diacylglycerol; DGAT2, diacylglycerol O-Acyltransferase 2;
DNL, de novo lipogenesis; ECs, endocannabinoids; ER, endoplasmic reticulum; FA, fatty acid; FA, fatty acids; FABPpm, fatty acid binding
protein; FASN, fatty acid synthase; FATP, fatty acid transport protein; FFA, free fatty acids; G6Pase, Glucose 6-phosphatase; GLUT, glucose
transporter; HDL, high density lipoprotein; HL, hepatic lipase; HSC, hepatic stellate cells; HSL, hormone sensitive lipase; IL, interleukin;
IRS, insulin receptor substrate; JNK, Jun N-terminal kinase; LDL, low density lipoprotein; LDLR, LDL receptor; LOX, lipoxygenase; LPL,
lipoprotein lipase; MCP1, monocyte chemoattractant protein-1; MTP, microsomal triglyceride transfer protein; NAFLD, non-alcoholic
fatty liver disease; NASH, non-alcoholic steatohepatitis; NF-B, nuclear factor-B; NO, nitric oxide; NOS, nitric oxide synthases; Nrf2,
nuclear factor E2-related factor 2; PEPCK, phosphoenolpyruvate carboxykinase; PGE2, prostaglandin E2; PI3K, phosphoinositol 3-kinase;
PKC, Protein kinase C; PNPLA3, patatin-like phosholipase domain-containing 3; PPAR, proliferator-activated receptor; PUFA,
polyunsaturated fatty acids; ROS, reactive oxygen species; SFA, Saturated fatty acid; SREBP, sterol regulatory element-binding protein;
TG, triglycerides; TLR4, Toll-like receptor 4; TNF, tumor necrosis factor alpha; VLDL, very low-density lipoprotein; WAT, white adipose tissue.
Corresponding author at: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 1st Floor B Block,
Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Tel.: +44 20 8383 8574; fax: + 44 20 8383 3212.
E-mail addresses: isabella.reccia@gmail.com (I. Reccia), drjayantsun19@gmail.com (J. Kumar), cherif.akladios@gmail.com (C. Akladios),
francesco.virdis@hotmail.it (F. Virdis), madhava.pai04@imperial.ac.uk (M. Pai), nagy.habib@imperial.ac.uk (N. Habib),
d.spalding@imperial.ac.uk (D. Spalding).

http://dx.doi.org/10.1016/j.metabol.2017.04.011
0026-0495/ 2017 Elsevier Inc. All rights reserved.
M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08 95

2.2. Hepatic Lipid Metabolism in NAFLD: Triglyceride Accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . 96


2.3. The Role of White Adipose Tissue in the Development of NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . 96
3. Insulin Resistance and NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
3.1. Insulin Action and Insulin Resistance in the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
3.2. Insulin Resistance and NAFLD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4. Other Factors Contributing to NAFLD Development and Progression to NASH. . . . . . . . . . . . . . . . . . . . . . . 99
4.1. Adipokines, Inflammation and Progression to NASH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4.2. The Role of Oxidative Stress in NAFLD Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
4.3. Insulin Resistance in Skeletal Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
5. Systemic Correlation Network of NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Authors'
. Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Appendix A. Supplementary Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

1. Introduction increased endogenous synthesis of FAs. Dietary intake affects


the metabolism of the human body and plays a pre-eminent
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad role in the development and progression of NAFLD [8]. Both
spectrum of liver disorders characterized by fatty deposition in energy intake and diet composition are indispensable in the
the liver in the absence of infection or significant alcohol intake genesis of metabolic disease. Whilst saturated FA and trans-
[1]. It has a varied histological spectrum, from fat accumulation FA have adverse effects on lipid and glucose metabolism,
within hepatocytes to steatohepatitis, which may have associ- monounsaturated FA and polyunsaturated FA (PUFA) seem to
ated fibrosis [1]. A significant proportion of people with NAFLD decrease insulin resistance, hepatic steatosis and inflamma-
(2030%) develop nonalcoholic steatohepatitis (NASH), which tion in NAFLD patients [911]. Saturated FA (SFA) and trans-FA
may lead to progressive liver fibrosis and cirrhosis, and may promote inflammation due to lipotoxicity in the liver,
hepatocellular carcinoma [2]. NASH carries a 20% potential and alter intestinal microbial flora leading to endotoxemia
risk of evolving further into cirrhosis, and thus it has become a [12]. Saturated FAs induce endoplasmic reticulum (ER) stress
leading cause of cryptogenic cirrhosis [2]. and lead to cellular dysfunction and apoptosis [13]. Converse-
The pathogenesis of NAFLD has not been fully elucidated. The ly, PUFA positively modulate the expression of several genes
liver has a central role in the regulation of lipogenesis, involved in hepatic lipogenesis and oxidation of FA, such as
gluconeogenesis and cholesterol metabolism [3]. Hepatic lipid sterol regulatory element-binding proteins (SREBP) and per-
and glucose metabolism is closely interrelated in the pathogen- oxisome proliferator-activated receptor (PPAR) alpha [14,15].
esis of liver disease and plays a significant role in the induction of PUFA are precursors to eicosanoids that control inflammation
inflammatory, proliferative and apoptotic signal pathways with- and immunity. Amongst them, n-6 PUFA (also known as
in the liver [3]. The most widely accepted theory links metabolic omega-6) are pro-inflammatory, whilst n-3 PUFA (omega-3)
syndrome, i.e. insulin resistance, to the development of hepatic have anti-inflammatory properties [16]. Eicosanoids play an
steatosis and the progression to steatohepatitis [4]. Insulin important role in the regulation of inflammation, and are
resistance, obesity and fatty liver are arranged in a kindred involved in several diseases, such as atherosclerosis, obesity,
fashion, making an environment conducive to the development NAFLD and cancer [17,18].
and progression of metabolic syndrome. NAFLD is common PUFA are metabolized by cyclooxygenase (COX) and
amongst obese and diabetic patients, but can also be found in the lipoxygenase (LOX) into different types of eicosanoids. Proin-
absence of these conditions [5]. NAFLD represents the hepatic flammatory eicosanoids include prostaglandin E2 (PGE2),
component of metabolic syndrome. Patients with metabolic which contributes to fat accumulation in the liver but can
syndrome, however, are heterogeneous and have different also induce COX2 enzyme leading to synthesis of interleukin
expressions of the disease [6,7]. (IL) 6; and leukotriene B4, which increases the production of
In this review, we focus on the pathogenesis of NAFLD and reactive oxygen species (ROS) and inflammatory cytokines
its systemic correlation, and aim to explore the possible [1921]. COX2 induces several inflammatory mediators that
future scenario of reducing the burden of the disease via the are pro-fibrotic, being expressed in activated hepatic stellate
application of a better understanding of the disease process. cells, and contributes to apoptosis, necrosis, inflammation
and fibrosis [22,23]. The n-6:n-3 PUFA ratio is increased in
many chronic inflammatory diseases, as well as in NAFLD,
2. Changes in Metabolism Contributing to due to dietary imbalance. Studies have shown the potential
NAFLD role of n-3 PUFA in reversing many hepatic pathological
changes induced by a high-fat diet in obese mice and NAFLD
2.1. Energy Intake and Diet Composition patients [24,25].
Dietary cholesterol also contributes to the development of
Most lipids that accumulate within the liver are derived from hepatic steatosis and inflammation by alteration of mitochon-
both increased uptake of circulating fatty acids (FAs), and drial function and modification of hepatic lipid composition
96 M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08

[26]. Alterations in cholesterol metabolism may contribute to FAs into TG for storage [47]. With excessive dietary calorie
disease severity and cardiovascular risk in NAFLD patients, as it intake, more FAs are stored within WAT. Lipoprotein lipase
can promote oxidative stress and progression to NASH [27,28]. (LPL) activity, which contributes to lipid storage in the fed state,
Several studies, however, have shown that fruitarians and lean is increased resulting in higher availability of free FAs for WAT
people can also develop NAFLD. It has been reported that even storage (Fig. 1) [48,49]. It has been shown that in obesity, LPL
in the absence of obesity, fructose can cause severe liver activity is increased in WAT [5052]. However, LPL becomes
damage, dyslipidemia, insulin resistance and progression to resistant to insulin action in extremely obese subjects or
NASH [29]. Fructose may increase hepatic de novo lipogenesis following chronic hyperinsulinemia [52].
(DNL) by upregulation of SREBP-1c and PPAR gamma, and may Studies have reported the crucial role of transport proteins
impair FA oxidation by downregulation of PPAR alpha, contrib- such as CD36, FATP and fatty acid binding protein (FABPpm),
uting to hepatic lipid accumulation [29]. Moreover, fructose that are overexpressed in obese patients [53]. While FATP and
can increase the transcription of phosphoenolpyruvate FABPpm are principally involved in FA transport, overexpres-
carboxykinase (PEPCK) and glucose transporter (GLUT) 2, sion of CD36 in macrophages and adipocytes contributes to
increasing hepatic gluconeogenesis and contributing to hepatic WAT inflammation and cell death (Fig. 1) [54]. As caloric intake
insulin resistance. It can also induce the production of increases, expression of enzymes involved in TG synthesis are
inflammatory mediators, oxidative stress, bacterial overgrowth enhanced and cause further enlargement in adipocytes in order
and progression to NASH [30,31]. to store excessive TG [55]. With increase in adiposity, adipo-
cytes become dysfunctional via the action of cytokines and
2.2. Hepatic Lipid Metabolism in NAFLD: Triglyceride insulin resistance [55]. Normally, insulin inhibits adipocyte
Accumulation lipolysis via suppression of the hormone-sensitive lipase (HSL)
[56]. In obesity and during insulin resistance, HSL is not
Triglyceride (TG) accumulation within hepatocytes is crucial inhibited, resulting in enhanced lipolysis, reduced glucose
in NAFLD [32]. Fatty acids that accumulate in the liver are uptake and impaired re-esterification of FAs (Fig. 1) [57,58].
derived from both peripheral lipolysis (free FA) following The impairment of adipocyte function and the production of
excessive food intake, and from increased DNL, a complex inflammatory mediators, such as tumor necrosis factor alpha
pathway synthesizing FA from glucose that can induce (TNF), can reduce the expression of PPAR gamma, which is
significant metabolic alterations if deranged [3235]. In the essential for adipogenesis and lipogenesis, and can impair TG
liver, the rate of free FA uptake from serum depends on the storage in WAT [55,59]. Importantly, PPAR gamma in WAT is
serum concentration of FAs and on the ability of hepatocytes also downregulated in the presence of insulin resistance and
to internalize FAs [34]. Fatty acid transport proteins (FATP) obesity.
and fatty acid translocase (CD36) are principally involved in The alteration of glucose metabolism in WAT is also
FA uptake and are overexpressed in NAFLD (Fig. 1) important in insulin resistance, as GLUT4 expression is
[33,34,36,37]. With excessive energy intake, FA esterification reduced in WAT in the presence of insulin resistance (Fig. 1)
in the liver is enhanced with a subsequent increase in TG [58]. It has been reported that enhanced DNL in WAT is
production via diacylglycerol O-acyltransferase 2, an enzyme associated with improved glucose tolerance and insulin
overexpressed in NAFLD [38,39]. sensitivity in mice and humans [58,60]. In healthy individuals,
Several other alterations in hepatic lipid composition and DNL contributes minimally to FA production in WAT [61].
FA metabolism have been demonstrated in NAFLD [40,41]. SREBP-1c and carbohydrate-responsive element-binding pro-
Increases in diacylglycerol (DAG), free cholesterol, n-6:n-3 tein (ChREBP) are both overexpressed in fatty liver, with
PUFA ratio, decreases in phosphatidylcholine and arachidonic SREBP-1c being a primary regulator of DNL in the liver, but not
acid, and the alteration of endogenous desaturase activity in WAT [58]. Whilst knockdown of hepatic ChREBP in
could all play a vital role in the progression to NASH [41,42]. genetically obese ob/ob mice markedly improves insulin
Glucose and fructose uptake is also enhanced in NAFLD. In resistance and liver steatosis, the induction of ChREBP in
the liver, GLUT2 regulates the influx of glucose in relation to WAT improves insulin sensitivity [57]. As DNL in WAT may be
the feeding state. Increased expression of GLUT2 has been important in glucose clearance and in regulating glycemia, it
noted with hyperglycemia, diabetes and NAFLD [43,44]. is possible that ChREBP-induced DNL in WAT may have a
GLUT5, primarily a fructose carrier, is also expressed in the positive effect on systemic insulin sensitivity [57].
liver [45]. Although hepatic specific deregulation of GLUT5 in
NAFLD has not yet been investigated, GLUT5 may also be
involved in the pathogenesis of NAFLD (Fig. 1).
3. Insulin Resistance and NAFLD
2.3. The Role of White Adipose Tissue in the Development
of NAFLD 3.1. Insulin Action and Insulin Resistance in the Liver

White adipose tissue (WAT) plays an active role in energy Non-alcoholic fatty liver disease is frequently associated with
balance. It stores fat as TG during excessive food intake and features of insulin resistance [62]. For a long time, skeletal
releases free FAs into the circulation when energy is needed muscle has been considered the primary source of insulin
[46]. Fatty acids in WAT derive from both serum uptake and resistance [6]. It has now been proposed, however, that skeletal
DNL. In normal conditions, insulin stimulates GLUT4-mediated muscle does not contribute to increased cardiovascular risk in
glucose uptake in WAT and promotes re-esterification of free the same way as the liver [62]. The liver is the central regulator
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Fig. 1 Changes in white adipose tissue metabolism and development of fatty liver. WAT stores FA in the form of TG. When
dietary intake is in excess, more FA are delivered to WAT as chylomicrons and lipoproteins, which contain ApoCII. ApoCII is
recognized by LPL, and this hydrolyzes TG back to FA. LPL activity is enhanced during calorie intake by several factors,
including insulin. Membrane transporters take up FA, instead of being re-esterified as TG; lipolysis is increased due to insulin
resistance and lipid overload. FA are then released into the circulation contributing to insulin resistance and fatty liver.
Glucose uptake is reduced by downregulation of GLUT4. Glucose activates ChREBP. ChREBP enhances WAT DNL, which
contributes to insulin sensitivity and improves glucose metabolism. Insulin resistance and CD36 overexpression induce
macrophage accumulation and inflammation of WAT, which in turn releases several mediators that induce progression to
NASH and worsen insulin resistance. Abbreviations: ApoCII: apolipoprotein C-II ChREBP: carbohydrate-responsive element-
binding protein; DGAT2: diacylglycerol O-Acyltransferase 2; DNL: de novo lipogenesis; FA: fatty acid; FABPpm: fatty acid
binding protein; FATP: fatty acid transport protein; GLUT: glucose transporter; HSL: hormone sensitive lipase; LPL: lipoprotein
lipase; NASH: non-alcoholic steatohepatitis; PEPCK: phosphoenolpyruvate carboxykinase; TG: triglyceride; WAT: white
adipose tissue.

of glucose and lipid metabolism and is particularly sensitive to which may be common to all FAs, it has been proposed that
insulin action [6]. Hepatic insulin resistance is associated with excessive intake of saturated fat causes hepatic insulin
accumulation of TG and FA metabolites within the liver, such as resistance via activation of the toll-like receptor 4 (TLR4)/
fatty acyl-CoA, DAG, ceramides, and glycosphingolipid (Fig. 2) MyD88 pathway. The TLR4 is a pro-inflammatory receptor,
[63]. In normal conditions, insulin stimulates tyrosine kinase and its activation by the adaptor protein MyD88 induces
activity of the insulin receptor, leading to phosphorylation of activation of IB kinase, de novo synthesis of ceramides,
insulin receptor substrates (IRS) 1 and 2, with activation of accumulation of ceramides and ceramides-mediated activation
downstream events that mediate the action of insulin [64]. of protein phosphatase 2A, which directly inhibits insulin
In fatty liver DAG activates protein kinase C (PKC), which signaling at the level of Akt phosphorylation (Fig. 2) [66,67].
subsequently inhibits the insulin receptor kinase. Phosphory- Hepatic insulin resistance leads to an increase in glucose
lation of IRS1 and IRS2 is then reduced, and their action is production and hyperglycemia (Fig. 2) [68]. In addition, hepatic
blocked. Activation of phosphoinositol 3-kinase (PI3K) and lipid and lipoprotein metabolism is also severely affected [69].
protein kinase Akt2 is also reduced, with the release of glucose In NAFLD, insulin resistance contributes to increased hepatic
via GLUT2 into the circulation (Fig. 2) [63,65]. The exact FA uptake via the action of insulin on CD36, and via increased
mechanism that induces liver insulin resistance is still contro- lipolysis in WAT [32]. Hyperinsulinemia induces an increase in
versial. Instead of the DAG-PKCdependent mechanism, FA synthesis via DNL, by expression of SREBP-1c in the liver
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Fig. 2 Mechanism of hepatic insulin resistance. As a consequence of TG accumulation and production of toxic metabolites,
mitochondrial dysfunction and oxidative stress occur. Toxic metabolites (diacylglycerol and ceramides) are produced in the
liver and interfere with the activation of insulin receptors (IRS1 and 2). The cascade of events that follows the activation of IRS
is blocked. This activation is also impaired by the activation of JNK via oxidative stress. The liver becomes resistant to insulin
action. Glycogen synthesis is reduced while gluconeogenesis is increased, and glucose is transported outside the liver via
GLUT2, with subsequent hyperglycemia. Hepatic insulin resistance also alters the metabolism of lipids. Uptake of FA is
increased, DNL is induced via insulin-activation of SREBP-1c and beta-oxidation is impaired, with induction of peroxisomal
and microsomal oxidation. The liver tries to compensate the increase in TG by enhancing the export of TG as VLDL through the
action of MTP. CETP and HL convert serum VLDL into atherogenic LDL that is not cleared from blood due to a lower affinity for
hepatic LDLR. This leads to hypertriglyceridemia, decreased HDL and increased LDL. Abbreviations: ACC: acetyl-CoA
carboxylase; ApoB: apolipoprotein B; CETP: cholesteryl ester transfer protein; CPT1: carnitine palmitoyltransferase 1; DAG:
diacylglycerol; FASN: fatty acid synthase; FFA: free fatty acid; G6Pase: Glucose 6-phosphatase; GLUT2: glucose transporter; HL:
hepatic lipase; IRS: insulin receptor substrate; JNK: Jun N-terminal kinase; LDLR: LDL receptor; MTP: microsomal triglyceride
transfer protein; PEPCK: phosphoenolpyruvate carboxykinase; PI3K: phosphoinositol 3-kinase; PKC: Protein kinase C;
SREBP: sterol regulatory element-binding protein; TG: triglyceride; TLR4: Toll-like receptor 4.

[3,33]. Moreover, beta-oxidation is also impaired due to the overproduction of toxic lipid metabolites, which can then further
enhanced production of malonyl-coA via acetyl-CoA carboxylase impair the action of insulin [74]. Oxidative stress, along with
2 (ACC2), which is also induced by SREBP-1c. Malonyl-coA inhibits other noxious stimuli, can cause activation of the Jun N-terminal
the enzyme carnitine palmitoyltransferase 1 (CPT1), which kinase (JNK), leading to IRS inactivation. In NASH, activation of
regulates beta-oxidation of FAs in mitochondria (Fig. 2) [33]. JNK is responsible for insulin resistance, lipoapoptosis and
Mitochondrial beta-oxidation, however, can be augmented in fibrosis [7577].
insulin resistance-associated NASH, as a compensatory mecha- Apoptosis is a complex process and a key feature in the
nism to increased uptake and synthesis of FAs [70]. This involves pathogenesis of NAFLD. Imbalance in apoptosis regulation is an
activation of PPAR alpha and enhanced activity of CPT1, which important mechanism inducing progression of liver damage
can be stimulated by PPAR alpha, CPT1 may also lose its affinity [78]. Several factors (i.e. SFA, PUFA) can induce apoptosis in
for malonyl-coA [7072]. Mitochondrial dysfunction, in particular NAFLD via different signaling pathways, including the mem-
deficiency in the respiratory chain, leads to overproduction of brane death receptor-mediated cascade (extrinsic pathway),
ROS, which then damage several components of the cell, causing ROS formation, ER stress, and lysosomal and mitochondrial
oxidative stress and eventually apoptosis [73]. Mitochondrial dysfunction (intrinsic pathway) [13,22,23,7577,79]. In the liver,
dysfunction can also cause insulin resistance and induce apoptosis promotes inflammation, fibrosis and cirrhosis, whilst
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in peripheral tissues such as WAT, skeletal muscle and the In obese and diabetic patients, peripheral insulin resistance
pancreas, apoptotic signals may contribute to the development may be initially responsible for the accumulation of fat in the
of insulin resistance [8084]. liver, whilst diet can be the primary cause of hepatic steatosis
An increase in hepatic fat is also associated with enhanced and hepatic insulin resistance in non-obese patients.
very low-density lipoprotein (VLDL) secretion from the liver in
an attempt to maintain hepatic lipid homeostasis [33]. This
mechanism is mediated by microsomal triglyceride transfer
protein (MTP), a key enzyme in the assembly and secretion of 4. Other Factors Contributing to NAFLD
VLDL, that regulates the incorporation of TG into apolipoprotein Development and Progression to NASH
B (ApoB) [85]. TG-rich VLDL is converted to LDL (low density
lipoprotein) in the circulation by cholesteryl ester transfer 4.1. Adipokines, Inflammation and Progression to NASH
protein (CETP) [86]. In normal conditions, LDL is removed from
the circulation by LDL receptors in the liver [33]. LDL receptor Adipose tissue remodeling is a continuous process that is
activity is reduced in NAFLD, whilst in NASH, MTP activity is pathologically accelerated in obesity [100]. Healthy WAT is
reduced and VLDL secretion is impaired, with further retention composed of adipocytes and stromal cells, such as
of TG within hepatocytes [85,87]. preadipocytes, endothelial cells, and immune cells that interact
with adipocytes in the secretion of adipokines [100102]. In
3.2. Insulin Resistance and NAFLD normal conditions, expansion of WAT involves recruitment of
adipogenic precursor cells, an adequate angiogenic response
The liver is responsible for maintaining normal glucose levels and appropriate remodeling of the extracellular matrix, all of
during fasting. Hepatic accumulation of lipids reduces hepatic which are essential for the expandability and functional
responsiveness to insulin, resulting in an increase of serum levels integrity of WAT [101,103]. In obesity, WAT expands massively,
of glucose and thus of insulin, producing a state of chronic existing adipocytes enlarge, angiogenesis and normal remod-
hyperinsulinemia [88]. Whether insulin resistance triggers lipid eling of extracellular matrix does not occur in a sufficient way to
accumulation in the liver, or whether fat deposition in the liver ensure adequate blood perfusion, resulting in hypoxia, which
alters the hepatic response to insulin, is not clear [6,88]. induces inflammatory and fibrotic changes in WAT [103106].
Hepatic FAs can derive from diet, from peripheral lipolysis Enlarged and inflamed WAT is characterized by macrophage
and from DNL. In patients with a high-fat diet, diet itself could infiltration [103,106,107]. Adipose macrophages produce several
be responsible for accumulation of lipids in the liver and the inflammatory cytokines that contribute to the alteration in
development of NAFLD, as demonstrated by several animal production of adipokines and the pathogenesis of obesity-
models [89]. In addition, dietary sugars enhance the endoge- induced insulin resistance and NASH [107]. Adipokines are
nous synthesis of FAs by inducing hepatic DNL [90]. As involved in body weight homeostasis, inflammation, coagula-
previously highlighted, several other dietary components can tion, fibrinolysis, insulin resistance, diabetes, atherosclerosis,
contribute differently to the pathogenesis of NAFLD [91]. A high and cancer [108,109]. When visceral adiposity is increased, WAT
calorie intake results in obesity and insulin resistance, with produces more pro-inflammatory cytokines, such as TNF, IL-6,
direct stimulation of hepatic DNL via SREBP-1c and deregulated and C reactive protein, whilst the production of adiponectin, a
peripheral lipolysis with increased delivery of free FAs to the protective adipokine, is decreased (Fig. 3) [110]. Adiponectin is
liver, as demonstrated by the fact that NAFLD patients have mainly produced by adipocytes and has many important
increased levels of free FAs [92]. In NAFLD patients, elevated effects, including suppression of hepatic glucose production
serum levels of free FAs are associated with features of and hepatic lipogenesis, stimulation of glucose uptake by
metabolic syndrome, in particular obesity, hyperglycemia and skeletal muscle, stimulation of FA oxidation in the liver and
hypertriglyceridemia, the levels correlate with the degree of skeletal muscle, stimulation of insulin secretion and inhibition
inflammation and the severity of liver damage [93]. of pro-inflammatory cytokines (IL-6 and TNF) [100].
There is a group of patients with NAFLD, however, that are Adiponectin improves insulin resistance by acting on the liver
not obese [94,95]. Although visceral fat is also increased in and skeletal muscle, as shown in obese animals [111].
lean patients with NAFLD, insulin resistance or alterations in Adiponectin binds to two specific receptors, AdipoR1 in skeletal
adipokines secretion are not always found. In this subgroup of muscle, and AdipoR2, that is mostly expressed in the liver [112].
patients, dietary components (i.e. excessive intake of choles- In the liver, AdipoR2 interacts with APPL-1 (adaptor protein
terol and reduced intake of PUFA) may have a major influence containing pleckstrin homology domain, phosphotyrosine-
in the early development of hepatic insulin resistance, and binding domain and a leucine zipper motif), which is involved
may be a key factor in the development of NAFLD and its in insulin signaling pathways. APPL-1 activation triggers a
subsequent metabolic alterations [94,96,97]. In this context, cascade of events mediated by 5-AMP-activated protein kinase
hyperinsulinemia is probably a consequence rather than a and PPAR alpha, that lead to a change in the expression of
cause of NAFLD [88,98]. It has recently been shown that lean several genes involved in glucose and lipid metabolism [113].
patients with NAFLD have more severe liver inflammation NAFLD patients have decreased serum levels of adiponectin
and higher mortality rates than obese NAFLD patients [99]. It and reduced hepatic expression of adiponectin receptors,
may be that obese and lean patients with NAFLD represent indicating a condition of adiponectin resistance [112,114].
two distinct clinicopathogenic subgroups, with different Adiponectin is also known to have antifibrotic and anti-
genetic, environmental and several other factors, all influenc- inflammatory effects; a number of studies have shown that
ing the pathogenesis and prognosis of the disease. patients with advanced fibrosis have low serum levels of
100 M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08

Fig. 3 Interrelation between various organs in the pathogenesis of NAFLD and progression to NASH. Both development of
NAFLD and progression to NASH result from the interaction between multiple organs and from different mechanisms of
damage, indicating that NAFLD is a systemic disease that is caused by several mechanisms and that induces many
dysfunctions in the whole body. Abbreviations: ECs: endocannabinoids; FA: fatty acid; FFA: free fatty acid; HDL: high density
lipoprotein; HSC: hepatic stellate cells; IRS: insulin receptor substrate; LDL: low density lipoprotein; MCP1: monocyte
chemoattractant protein-1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; TG: triglycerides;
VLDL: very low-density lipoprotein; WAT: white adipose tissue.

adiponectin [115,116]. In the liver, inflammatory cytokines are secretion [100]. Leptin deficiency in animal models is associ-
produced by Kupffer cells and hepatic stellate cells (HSC); these ated with obesity, diabetes and NAFLD [120122]. Obese and
cytokines induce inflammation, cell death and fibrosis (Fig. 3) NAFLD patients, however, have increased levels of leptin, as a
[117]. In healthy subjects, adiponectin stimulates the produc- result of leptin resistance (Fig. 3) [120,123].
tion of anti-inflammatory cytokines (IL-10), and reduces levels The presence of steatohepatitis is the most important factor
of pro-inflammatory cytokines (IL-6 and TNF) by suppressing for progression to cirrhosis and end-stage liver disease in NAFLD.
activation of Kupffer cells and HSC; it may therefore ameliorate Non-alcoholic steatohepatitis is characterized by hepatic and
NASH and hepatic fibrosis [118]. The lack of adiponectin systemic activation of immune and inflammatory responses
aggravates NASH, whilst adiponectin administration prevents mediated by crosstalk between the liver, the gut and adipose
progression to NASH in animal models [119]. tissue [124]. The liver is able to produce a strong inflammatory
Another important protein in healthy WAT is leptin. response to several insults by activation of Kupffer cells,
Leptin is expressed mainly in adipose tissue and interacts TLRs, lymphocytes, neutrophils and inflammasome [125,126].
with different receptors in the central nervous system and Lipotoxicity is an important factor that leads to inflammation in
peripheral tissues, including the liver [100,119]. Secretion of the liver. However, not all of the patients with NAFLD progress to
leptin is also proportional to body adiposity. Leptin inhibits NASH. It seems possible that inflammation originates outside
food intake and increases energy expenditure via hypotha- the liver and that alterations in intestinal microbial flora,
lamic pathways when energy is in excess [100]. In addition, inflammation in WAT and circulating inflammatory cells also
leptin suppresses hepatic glucose production and FA synthe- play an important role [126]. It is now also evident that a genetic
sis, stimulates FA oxidation in the liver and skeletal muscle, it predisposition to NAFLD, NASH and their complications exists.
also enables glucose uptake in skeletal muscle and insulin Patients with the patatin-like phosholipase domain-containing 3
M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08 101

(PNPLA3) gene variant I148M have an increased risk of develop- production of pro-inflammatory cytokines (especially TNF)
ing NAFLD and subsequent progression to NASH; they also have and ROS, infiltration of monocytes within the liver, and
a greater amount of fat deposition in the liver, and have a more alteration of the C-JNK and nuclear factor-B (NF-B) path-
severe histology in terms of necro-inflammation and fibrosis ways, all promoting NASH progression [142147].
[127129]. The pathogenesis of NASH is a complex process that It has also been shown that trans-FA and fructose
starts with TG accumulation in the liver, and progresses to can directly induce hepatic steatosis and inflammation
inflammation and fibrosis via several mechanisms as described [10,30,31,148]. Fructose can directly alter the composition of
by the multiple parallel hits hypothesis [130]. In the first stages, gut microbiota, resulting in acquisition of a westernized
hepatic TG accumulation represents a benign process as TGs are microbiome with impaired metabolic capacity [149]. Finally,
considered to be an inert source of energy storage. With lipid WAT inflammation and alteration of secretion of adipokines
overload, however, lipid metabolism becomes deranged and also contribute to the development of NASH.
lipotoxicity is induced (Fig. 3) [131].
A high calorie diet enriched in fat and fructose, alters 4.2. The Role of Oxidative Stress in NAFLD Progression
microbial flora in the small intestine (gut microbiota), promot-
ing intestinal inflammation and increasing gut permeability Oxidative stress is due to an imbalance between ROS and
[132]. The gut and the liver are closely associated, communi- antioxidant systems [150]. Several pathophysiological events
cating via several mediators [133]. Integrity of the intestinal can trigger the production of free radicals in the liver, such as
barrier is essential in the maintenance of a healthy gutliver lipid peroxidation, hyperinsulinemia and hepatic iron over-
axis [134]. Patients with biopsy-proven NAFLD have increased load [151153]. Mitochondria are a major source of ROS in
intestinal permeability with disrupted intercellular tight junc- NAFLD, and mitochondrial dysfunction is crucial to the onset
tions in comparison with healthy controls [135]. Commensal and progression of NASH [154]. Patients with NASH have
microflora normally provides a barrier effect in the gut, swollen mitochondria with structural alterations, impaired
inhibiting colonization by pathogenic bacteria. In patients respiratory chain and deranged beta-oxidation [155]. Several
with NAFLD, and in several other diseases, there is an chronic diseases, such as obesity, metabolic syndrome and
imbalance between normal and pathogenic bacteria in the gut fatty liver, are associated with oxidative stress. In the liver,
[136]. Human microbiota is a dynamic community that is oxidative stress triggers an inflammatory cascade that
susceptible to changes in environment and lifestyle. The produces progressive liver damage [156]. Patients with
composition of gut microbiota is different in obese and lean steatohepatitis have reduced glutathione levels, decreased
individuals, and in patients with NASH and cirrhosis [137]. superoxide dismutase and catalase activity, and increased
Patients with NASH have a lower percentage of bacteroides in levels of hepatic cytochrome P450 2EI [157].
their stools, and an increased presence of Clostridium ROS-mediated cell injury includes DNA damage, oxidation
coccoides and alcohol-producing microbiota, such as Escherichia of FAs in lipids causing disruption of cell membrane integrity,
coli, with ethanol significantly contributing to gut permeability oxidation of amino acids in proteins causing protein instability,
and to hepatotoxicity [138140]. and release of pro-inflammatory cytokines [158]. Endoplasmic
The gutliver axis plays a central role in the pathogenesis of reticulum and peroxisomes in the liver, however, have a greater
obesity and NAFLD, as intestinal microbiota interacts with the capacity to produce ROS [159]. In NAFLD, there is an increased
host immune system modulating intestinal permeability, deposition of FAs in the liver, whilst mitochondrial FA oxidation
inflammation, and insulin resistance [132]. Gut microbiota is altered with compensatory peroxisomal -oxidation and
contributes to the pathophysiology of NAFLD in a number of microsomal -oxidation to reduce FA accumulation. Enhanced
different ways: by increasing body weight and FA synthesis, by oxidation in peroxisomes and microsomes, as well as in
contributing to insulin resistance, by alteration of the metabo- mitochondria, however, significantly contributes to greater
lism of choline with a subsequent reduction in hepatic VLDL production of ROS in NAFLD [160]. In the liver, lipid peroxidation
secretion, and by modification of bile acid metabolism [133]. results in production of aldehyde from PUFA. ROS and aldehyde
Moreover, bacterial and endotoxin translocation secondary to can activate HSC leading to fibrosis and persistent chronic
increased gut permeability triggers the production of pro- inflammation [161]. Kupffer cells are also an important source
inflammatory molecules (i.e. lipopolysaccharide) and cytokines of ROS, nitric oxide (NO), cytokines and metalloproteinases,
that are hepatotoxic; these may be implicated in the develop- that can activate HSC inducing collagen synthesis and
ment of insulin resistance and NASH [134]. In addition, gut fibrogenesis [162]. In addition, although still controversial,
microbiota endotoxins, such as lipopolysaccharide, interact hepatic iron overload may also have a role in the development
with innate immune sensors, specifically with TLR4, mediating of NASH, as patients with NASH have been shown to have
a state of chronic systemic, low-grade inflammation that higher levels of iron [163]. In NASH, iron may contribute to
affects the liver, WAT, the brain, islet cells and blood vessels, oxidative stress; it may induce necrosis of hepatocytes,
promoting NAFLD, insulin resistance, obesity, diabetes and inflammation via Kupffer cells, fibrosis secondary to activation
atherosclerosis [141]. The expression of TLR in macrophages of HSC and insulin resistance [164,165]. Conversely, iron
induces the production of TNF, IL-1b, chemokines and directly depletion may improve liver damage and insulin resistance in
stimulates the release of pro-fibrogenic factors by HSCs [140]. NAFLD patients [166,167].
In high-fat diet induced NAFLD, Kupffer cells are increased In oxidative stress, along with the overproduction of ROS,
in number and activated by lipopolysaccharide via TLR4, there is a reduction in the antioxidant capacity of cells, which is
CD14, and lipopolysaccharide binding protein, leading to regulated by the transcription factor nuclear factor E2-related
recruitment of leucocytes, activation of natural killer cells, factor 2 (Nrf2) [168]. Nrf2 activates the expression of several
102 M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08

antioxidant response elements, including NAD(P)H:quinone as TNF, IL-6, monocyte chemoattractant protein-1 (MCP-1) and
oxidoreductase-1, glutathione transferase, and glutamate cys- endocannabinoids (ECs), can disrupt skeletal muscle metabo-
teine ligase [169]. In the livers of patients with NAFLD, Nrf2 is lism and contribute to insulin resistance (Fig. 3) [187,189].
upregulated with subsequent increased expression of antioxi-
dant response elements; their antioxidant function, however, is
impaired with disease progression to NASH [170]. In Nrf2-null 5. Systemic Correlation Network of NAFLD
mice fed with a methionine and choline-deficient diet, fat
deposition was seen to be more severe, there were lower NAFLD represents an independent risk factor for cardiovas-
hepatic glutathione levels and enhanced lipid peroxidation, cular disease (CVD) [190]. CVD is an important cause of death
when compared to mice expressing Nrf2, and especially in in patients with NAFLD [191]. Non-alcoholic fatty liver disease
comparison with those where Nrf2 expression was enhanced and CVD are strongly related as they have several metabolic
[171]. Moreover, steatohepatitis was more severe and its derangements in common [192]. In addition, NAFLD directly
development was accelerated, suggesting that Nrf2 could influences the pathogenesis of CVD by the release of pro-
represent a potential therapeutic target in NAFLD [172,173]. atherogenic factors, and atherosclerosis is common and more
Activated macrophages also generate excessive NO severe in patients with NAFLD, especially in its more
through the oxidation of L-arginine by the inducible form of advanced stages [191,193,194]. The pathogenesis of CVD in
nitric oxide synthases (NOS). Nitric oxide is another potent patients with NAFLD is still unclear. Atherogenic dyslipid-
free radical with strong cytotoxic and genotoxic effects via emia, postprandial hyperlipidemia, endothelial dysfunction,
damage to proteins and DNA [174]. During oxidative stress, hypercoagulability, cardiac dysfunction, inflammation, oxi-
NO and superoxide can combine to form peroxynitrite, dative stress, low levels of adiponectin and chronic kidney
promoting nitration of tyrosine and damaging several cellular disease (CKD) can all contribute to the increased risk of CVD in
components [175,176]. Animals with fatty livers and obesity patients with NAFLD [190,193,195,196].
secondary to a high fat diet have an increased expression of Non-alcoholic fatty liver disease is also associated with an
inducible NOS which correlates to the presence of NASH and increased risk of CKD in patients with type 2 diabetes, and in
diabetes [177]. In NASH-related fibrosis, expression of induc- nondiabetic and nonhypertensive patients, independently of
ible NOS is increased, suggesting that NO may also have a role conventional risk factors for renal disease (i.e. duration and
in inducing hepatic fibrosis [178]. Finally, patients with NAFLD control of diabetes, cardiometabolic factors and medications)
and a polymorphism of the inducible form of NOS, have an [197,198]. As for CVD, NAFLD could be a marker of CKD [199].
increased risk of NAFLD and fibrosis [179]. Non-alcoholic fatty liver disease and especially NASH, how-
ever, are characterized by a state of chronic inflammation,
4.3. Insulin Resistance in Skeletal Muscle which could instead represent an independent risk factor for
CKD [200202].
Insulin resistance is defined as a reduced response to the Brain insulin resistance, neurodegeneration and cognitive
action of insulin of target tissues, such as the liver, skeletal impairment can all complicate obesity, type 2 diabetes and
muscle and adipose tissue [180]. Skeletal muscle is the NASH, as demonstrated in experimental models of NAFLD
predominant site of insulin-mediated glucose uptake in the [203205]. Patients with NASH have increased rates of neuro-
postprandial state, and is the major site for glycogen storage psychiatric disorders and are at risk of cognitive impairment
in humans [181]. Insulin resistance induces a reduction in [206,207]. Non-alcoholic fatty liver disease, obesity and insulin
glucose uptake and glycogen synthesis in skeletal muscle. resistance can induce a liver-brain axis of neurodegeneration
Dietary carbohydrates are therefore diverted from the muscle mediated by toxic lipids, such as ceramides, that can cross the
to the liver and promote DNL, contributing to hyperlipidemia bloodbrain barrier due to their lipid-soluble nature, leading to
and NAFLD [182,183]. progressive brain degeneration and cognitive impairment
Elevated levels of free FAs in serum are associated with [203,204] [208]. In addition, hyperinsulinemia causes progres-
skeletal muscle insulin resistance [184]. Several mechanisms sive injury to microvessels, producing a state of chronic cerebral
have been implicated in the pathogenesis of free FA-induced hypoperfusion [209]. Gut microbiota also communicate with
insulin resistance. Free FAs can directly stimulate the innate the brain via several different pathways and can influence brain
immune response via interaction with TLR4, which induces an function and behavior [210].
inflammatory cascade via NF-B, c-JNK and suppressors of Patients with fatty livers also have increased pancreatic fat
cytokine signaling pathways, with the consequent transcription content, a condition named non-alcoholic fatty pancreatic
of a variety of pro-inflammatory genes and the production of disease [83,211]. It is not clear whether excessive pancreatic
pro-inflammatory cytokines [183,185187]. An increase in skel- TG content (pancreatic steatosis) can cause beta-cell dysfunc-
etal muscle uptake of free FAs and/or a reduction in FA tion [212]. Intrapancreatic fat and increased levels of free FAs
oxidation due to mitochondrial dysfunction can also lead to can have a lipotoxic effect on islet beta-cells, causing impaired
intramyocellular accumulation of TG and lipid metabolites, insulin production and beta-cell apoptosis [83] [84]. In a multi-
such as long-chain fatty acyl-CoAs, DAG and ceramides. These ethnic sample of obese adults without diabetes, the correlation
metabolites can activate several kinases that interfere with the between pancreatic content of TGs and islet beta-cell dysfunc-
phosphorylation and activation of IRS, ultimately leading to a tion was related to the different ethnicity of patients, suggest-
reduction in muscle glucose uptake and glycogen synthesis ing a genetic predisposition for the development of pancreatic
[183,188]. Furthermore, the change in the secretion of steatosis [213]. Free FAs accumulate in several organs, including
adipokines with overproduction of inflammatory factors such the pancreas, but in contrast with other organs, the
M ET ABOL I S M CL IN I CA L A N D E XP E RI ME N TAL 7 2 ( 2 01 7 ) 9 41 08 103

contribution of FAs to the pathogenesis of islet beta-cell


dysfunction in humans is less clear. The increase in pancreatic Acknowledgements
lipid content may be a consequence, rather than the cause, of
impaired glucose metabolism in NAFLD and obese patients This research did not receive any specific grant from public,
[212]. commercial, or non-profit funding agencies.

Appendix A.
6. Conclusion Supplementary Data

Non-alcoholic fatty liver disease is a complex disease Supplementary data to this article can be found online at
caused by a number of different pathogenic processes as a http://dx.doi.org/10.1016/j.metabol.2017.04.011.
result of the systemic interaction between the liver and
several other organs. The liver has a central role in the
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