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Insulin also promotes hepatic FFA uptake and de novo lipogenesis. FFAs are only oxidized minimally
and are primarily re-esterified to triglycerides and then exported as VLDL [1]. In subjects with NAFLD,
VLDL secretion is often increased but it reaches a plateau, indicating a saturable process [1]. In
subjects with NAFLD, total body lipid oxidation and hepatic beta oxidation are increased [2]. We have
hypothesized that one of the mechanisms that leads to NAFLD is the presence of adipose tissue insulin
resistance that leads to fatty acid overflow, and the saturation of FFA oxidation and VLDL secretion that
promote hepatic fat accumulation (‘first hit’; Fig. 2) [1].
It has been proposed that steatosis progresses to NAFLD/NASH after a ‘second hit’ due to lipotoxicity
and oxidative stress (Fig. 2) [1]. Lipotoxicity impairs mitochondrial function and oxidation with the
production of ROS resulting in liver damage and impaired detoxification and repair abilities [1].
Not all fats are equal
In vitro data have shown that palmitate and saturated fatty acid (SFA) are known to induce lipotoxicity,
mainly by producing ROS, inducing cell damage, apoptosis and cell death in various types of cells,
including hepatic cells [6, 7]. Unsaturated fat (e.g., oleate) induces more steatosis with the formation of
triglyceride-enriched lipid droplets and autophagy, but with a minimal effect on apoptosis [7].
Plasma and tissue metabolomic analyses revealed that several classes of lipids are altered in subjects with
NAFLD/NASH [8, 9]. Subjects with NAFLD had increased plasma concentrations of triacylglycerides
(TAG), FFA [1] and phosphocholine (PC) as well as increased indexes of de novo lipogenesis and
desaturase activity (SCD1) [9], mainly due to hepatic and adipose tissue insulin resistance [1]. In
addition, NAFLD and NASH patients exhibit a progressive decrease in the concentrations of plasma
lysophosphocholines (LyPC) [8, 10], a reduction in total n-3 and n-6 polyunsaturated fatty acid (PUFA)
content across most lipid classes (FFA, TAG, PC, LyPC) and reduced peroxisomal activity [9].
Metabolomic analyses of human liver tissues are limited. It has been proposed that an excess of saturated
fat relative to unsaturated fat could be harmful to the hepatic metabolism. Confirming this hypothesis,
it has recently been published that in subjects with the PNPLA3 I148M allele, n-3 PUFA α-linolenic
acid content is increased while several n-6 PUFAs and saturated fatty acids were decreased in the liver
TAG fraction [11].The authors found a strong inverse correlation between n-6 PUFA and TAG content
independent of PNPLA3 genotype. The PNPLA3 I148M allele confers a predisposition to NAFLD
but protection against insulin resistance [12, 13]. It is likely that different fatty acids could promote or
reduce oxidative stress, since cellular models have shown that stearic acid is toxic and promotes insulin
resistance while α-linolenic acid is protective [11]. Metabolomic and lipidomic studies are ongoing to
search for plasma and tissue biomarkers that could predict and prevent the progression of NAFLD.
Conclusions
Subjects with NAFLD are not all obese but all tend to have visceral fat accumulation and ectopic fat
in other organs. For this reason NAFLD/NASH is a risk factor for both diabetes and CVD. Visceral
and ectopic fat are increased in subjects with ‘low expandability’ of subcutaneous fat and in those
with large adipocytes that are not only hypertrophic, but also resistant to the antilipolytic effect of
insulin, resulting in fatty acid overflow, inflammatory processes and eventually, adipocyte necrosis.
These events generate ‘signals’ (release of adipokines, hormones, other unknown factors) that locally
induce inflammation, recruit macrophages and increase ectopic fat accumulation, leading to lipotoxicity,
reduced mitochondrial activity and metabolic dysfunction in all tissues. Among the different classes of
lipids, saturated fats are more lipotoxic. Metabolomic and lipidomic studies are ongoing to evaluate
plasma biomarkers to predict and prevent the progression of NAFLD.
44 Postgraduate Course Syllabus • Metabolic Liver Disease
and are primarily re-esterified to triglycerides and then exported as VLDL [1]. In subjects with NAFLD,
VLDL secretion is often increased but it reaches a plateau, indicating a saturable process [1]. In
subjects with NAFLD, total body lipid oxidation and hepatic beta oxidation are increased [2]. We have
hypothesized that one of the mechanisms that leads to NAFLD is the presence of adipose tissue insulin
resistance that leads to fatty acid overflow, and the saturation of FFA oxidation and VLDL secretion that
promote hepatic fat accumulation (‘first hit’; Fig. 2) [1].
It has been proposed that steatosis progresses to NAFLD/NASH after a ‘second hit’ due to lipotoxicity
and oxidative stress (Fig. 2) [1]. Lipotoxicity impairs mitochondrial function and oxidation with the
production of ROS resulting in liver damage and impaired detoxification and repair abilities [1].
Not all fats are equal
In vitro data have shown that palmitate and saturated fatty acid (SFA) are known to induce lipotoxicity,
mainly by producing ROS, inducing cell damage, apoptosis and cell death in various types of cells,
including hepatic cells [6, 7]. Unsaturated fat (e.g., oleate) induces more steatosis with the formation of
triglyceride-enriched lipid droplets and autophagy, but with a minimal effect on apoptosis [7].
Plasma and tissue metabolomic analyses revealed that several classes of lipids are altered in subjects with
NAFLD/NASH [8, 9]. Subjects with NAFLD had increased plasma concentrations of triacylglycerides
(TAG), FFA [1] and phosphocholine (PC) as well as increased indexes of de novo lipogenesis and
desaturase activity (SCD1) [9], mainly due to hepatic and adipose tissue insulin resistance [1]. In
addition, NAFLD and NASH patients exhibit a progressive decrease in the concentrations of plasma
lysophosphocholines (LyPC) [8, 10], a reduction in total n-3 and n-6 polyunsaturated fatty acid (PUFA)
content across most lipid classes (FFA, TAG, PC, LyPC) and reduced peroxisomal activity [9].
Metabolomic analyses of human liver tissues are limited. It has been proposed that an excess of saturated
fat relative to unsaturated fat could be harmful to the hepatic metabolism. Confirming this hypothesis,
it has recently been published that in subjects with the PNPLA3 I148M allele, n-3 PUFA α-linolenic
acid content is increased while several n-6 PUFAs and saturated fatty acids were decreased in the liver
TAG fraction [11].The authors found a strong inverse correlation between n-6 PUFA and TAG content
independent of PNPLA3 genotype. The PNPLA3 I148M allele confers a predisposition to NAFLD
but protection against insulin resistance [12, 13]. It is likely that different fatty acids could promote or
reduce oxidative stress, since cellular models have shown that stearic acid is toxic and promotes insulin
resistance while α-linolenic acid is protective [11]. Metabolomic and lipidomic studies are ongoing to
search for plasma and tissue biomarkers that could predict and prevent the progression of NAFLD.
Conclusions
Subjects with NAFLD are not all obese but all tend to have visceral fat accumulation and ectopic fat
in other organs. For this reason NAFLD/NASH is a risk factor for both diabetes and CVD. Visceral
and ectopic fat are increased in subjects with ‘low expandability’ of subcutaneous fat and in those
with large adipocytes that are not only hypertrophic, but also resistant to the antilipolytic effect of
insulin, resulting in fatty acid overflow, inflammatory processes and eventually, adipocyte necrosis.
These events generate ‘signals’ (release of adipokines, hormones, other unknown factors) that locally
induce inflammation, recruit macrophages and increase ectopic fat accumulation, leading to lipotoxicity,
reduced mitochondrial activity and metabolic dysfunction in all tissues. Among the different classes of
lipids, saturated fats are more lipotoxic. Metabolomic and lipidomic studies are ongoing to evaluate
plasma biomarkers to predict and prevent the progression of NAFLD.
44 Postgraduate Course Syllabus • Metabolic Liver Disease
