For Part 1 see the previous post.
IV. Metabolic Consequences of Fatty Liver
A. Dyslipidemia
It has been shown convincingly that fatty liver is associated with insulin resistance, atherosclerosis, and the metabolic syndrome (15, 44, 49, 201, 202, 203, 204). Furthermore, fatty liver predicts future cardiovascular events (3, 201). It is thought that a pro-atherogenic serum lipid profile, which is commonly observed in subjects with fatty liver, is in part responsible for these relationships. This profile consists of low HDL cholesterol and high triglyceride levels, small, dense LDL particles, and high apolipoprotein B100 levels (4, 78, 205, 206, 207, 208). An increased rate of hepatic triglyceride synthesis and VLDL particle production, which secondarily results in low HDL cholesterol and increased LDL particle density (78, 209, 210), is considered to be causative for this type of dyslipidemia. Furthermore, a decrease in lipoprotein lipase activity may also be involved (211, 212).
Although there is evidence that insulin resistance is a strong underlying mechanism for this dyslipidemia (78, 207, 209, 210, 213, 214, 215), other studies suggest that fat accumulation in the liver may also have an independent effect on dyslipidemia. In the study by Toledo et al. (206), plasma insulin was higher in subjects with steatosis compared with controls, but insulin was much weaker correlated with serum triglycerides than hepatic steatosis. However, in that study hepatic insulin resistance was not measured, leaving the question open whether liver fat correlated with triglycerides also independent of hepatic insulin resistance. Regarding HDL, not only quantitative, but also qualitative and compositional alterations are related to its antiatherogenic properties (216, 217, 218, 219). Circulating HDL2 was particularly found to protect from atherosclerosis (220, 221).
We could recently show that fatty liver correlates more strongly with circulating HDL2 and the HDL2/HDL3 ratio than with total HDL (222). Moreover, the correlation of liver fat with HDL2 and the HDL2/HDL3 ratio remains statistically significant even after adjustment for whole-body insulin resistance and circulating adiponectin that is associated with both dyslipidemia and liver fat (64, 65). In agreement with the data from Toledo et al. (206) and with the limitation that hepatic insulin resistance was not directly measured, these findings suggest that there may be a direct link between fatty liver, dyslipidemia, and thus atherosclerosis.
B. Inflammation
Besides its metabolic functions, the liver is involved in immune responses (47, 223). Although the hepatocytes represent approximately two thirds of the total cells in the liver, other cell types are biliary epithelial cells, sinusoidal endothelial cells, Kupffer cells, stellate cells, dendritic cells, and lymphocytes (224, 225). The Kupffer cells and lymphocytes are the main cell types involved in the hepatic immune response. Kupffer cells represent the largest group of fixed macrophages in the body and account for about 20% of nonparenchymal cells in the liver (226). They are derived from circulating monocytes that arise from bone marrow progenitors (227). In the liver, Kupffer cells clear endotoxins (lipopolysaccharides) from the passing blood, and phagocyte debris and microorganisms. Furthermore, they are in close contact with blood lymphocytes and other resident antigen-presenting cells.
Kupffer cells produce cytokines that play a key role in cell differentiation and cell proliferation. This process is modulated by the membrane-bound bile acid receptor TGR5/mBAR (228). Kupffer cell-derived IL-12 and IL-18, for example, regulate natural killer (NK) cell differentiation and promote the local expansion of cytotoxic NK cell subpopulations that express large amounts of antiviral interferon (IFN)-γ (229). Other Kupffer cell-derived cytokines such as IL-1β, IL-6, TNF-α, and leukotrienes promote the infiltration and antimicrobial activity of neutrophils (230). Because NK T cells are capable of releasing IFN-γ and IL-4 (231), they are thought to modulate the local and systemic adaptive immune responses to either a proinflammatory type I (IFN-γ, TNF-α) or an antiinflammatory type II (IL-4, IL-10, IL-13) profile (224, 225). The increased production of TNF-α is considered to have a particularly major role in the pathogenesis of hepatic insulin resistance (232, 233).
In this aspect, the gastrointestinal tract may be important for hepatic inflammation and the pathophysiology of NASH. This is supported by data from animal studies (234) and from jejunoileal bypass surgery for morbid obesity in humans showing that NASH and fibrosis are encountered as a complication of this procedure (235, 236). Furthermore, small intestinal bacterial overgrowth was more frequently found in patients with NASH than in controls (237). Such derangement of the gut flora, which plays an important role in the prevention and treatment of infections as well as in immune functions, is also thought to be mediated by the consumption of manipulated and processed foods, e.g., high amounts of refined sugar and saturated fat and a decrease in fiber, vitamins, and antioxidants (238). Small intestinal bacterial overgrowth results in the production of ethanol in animals (239) and humans (240, 241, 242) as well as in the release of bacterial lipopolysaccharides (243). Both ethanol and lipopolysaccharides activate TNF-α production in Kupffer cells, thereby, inducing hepatic inflammation (244). In agreement with this hypothesis, antibiotics (245) and probiotics (246) targeting the gut flora positively affect hepatic inflammation in animals as well as in humans (235, 247).
Furthermore, hepatic inflammation is induced by hepatic steatosis. Hotamisligil (47) and Shoelson et al. (223) hypothesize that hepatic steatosis might induce a subacute inflammatory response in liver that is similar to the adipose tissue inflammation, after adipocyte lipid accumulation. Part of this process is considered to be attributed to endoplasmic reticulum (ER) and oxidative stress. The ER is a membranous network responsible for the processing and folding of newly synthesized proteins. Besides hypoxia, toxins, infections, and other insults, nutrient fluctuations and excess lipids pose stress on the ER that is accompanied by accumulation of unfolded or misfolded proteins (248). ER stress in liver and adipose tissue is generated in mice with genetic or diet-induced forms of obesity. This is largely mediated by activation of JNK resulting in impairment of insulin signaling (249). Furthermore, ER stress is associated with activation of multiple stress responses and with the specific activation of CREBP, a hepatocyte-specific bZip transcription factor that may have an important role in hepatic acute-phase response such as the induction of transcription of the serum amyloid P-component and C-reactive protein (CRP) genes (250).
In addition, the ER is involved in the generation of ROS and, consequently, oxidative stress (251). Furthermore, ROS are formed in the mitochondria by impaired mitochondrial respiratory chain capacity. Particularly an increase in cytosolic fatty acids results in increased fatty acid oxidation and, thus, ROS production (252, 253). In agreement, in humans with NASH, increased levels of by-products of lipid peroxidation are found, suggesting increased oxidative stress (254). Finally, under conditions of oxidative stress, NF-κB and JNK pathways are activated, representing a link between oxidative stress and insulin resistance (47, 223, 255).
Altogether, the close interaction of immune cells with the metabolically active hepatocytes (47, 223) may trigger local but also systemic subclinical inflammation, a process that is strongly regulated by PPARα (256). Systemic subclinical inflammation can be estimated by measurement of circulating CRP. The plasma levels of this acute-phase protein are very low under healthy conditions but increase in response to a pathological inflammatory process. Because of its relatively low half-life of 18 h, CRP represents a useful, early nonspecific marker of inflammation (257). Plasma CRP is produced predominantly by hepatocytes and is under transcriptional control by IL-6 and other proinflammatory cytokines. However, other sites of local CRP synthesis and possibly secretion have also been suggested (258). Circulating CRP is positively correlated with liver fat (259, 260, 261, 262). Moreover, CRP levels are higher in patients with histologically proven NASH compared with simple steatosis (262). Of interest, circulating CRP most probably is not merely an indicator of systemic inflammation but is also involved in the pathogenesis of atherosclerosis (257). These data suggest that fat accumulation in the liver may be involved in the pathophysiology of atherosclerosis via induction of systemic inflammation.
C. Insulin resistance
Fatty liver and obesity are strongly associated with insulin resistance (263, 264), the condition that plays a predominant role in the pathophysiology of type 2 diabetes (47, 255, 264, 265, 266) and cardiovascular disease (67, 267, 268, 269, 270). Animal studies reveal that fat accumulation in the liver inhibits insulin signaling in hepatocytes. In particular, hepatic insulin resistance can be attributed to impaired insulin-stimulated insulin receptor substrate (IRS)-1 and IRS-2 tyrosine phosphorylation resulting in increased gluconeogenesis (263, 271, 272). In humans, a strong relationship exists between fat accumulation in the liver and whole-body insulin resistance (4, 71, 80, 106, 146, 190, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285) (Fig. 3⇓). More importantly, liver fat correlates with insulin resistance independent of visceral adiposity (147, 286), a major regulator of both liver fat and insulin resistance (77, 287). Euglycemic, hyperinsulinemic clamp studies with tracer methods to measure the suppression of endogenous glucose production, an estimate of hepatic insulin sensitivity, show that liver fat is particularly strongly correlated with hepatic insulin sensitivity (41, 106, 147, 280, 288, 289).
Fig. 3.
Relationship of liver fat, measured by 1H-MRS, to insulin sensitivity. Liver fat content was quantified by localized 1H-MRS using a 1.5-T whole-body imager. Although there is no clear difference in gray shade in the liver between the individuals, the signal from the 1H-MRS shows that liver fat content is obviously different. These two individuals also behaved differently when insulin sensitivity was measured during the euglycemic-hyperinsulinemic clamp. The individual with higher liver fat content had lower insulin sensitivity. To correct this relationship for the confounding factors total body fat and body fat compartments, whole-body MR imaging for quantification of these parameters (inset) is a precise technique. [Adapted from N. Stefan et al.: Horm Res 64(Suppl 3):38–44 (285 ), with permission from S. Karger AG.]
Interestingly, hepatic steatosis is also associated with myocardial insulin resistance. In patients with type 2 diabetes, liver fat measured by 1H-MRS is the strongest predictor of insulin-stimulated myocardial glucose uptake, compared with other determinants such as visceral fat mass and whole-body glucose uptake (290). Moreover, liver fat is also strongly associated with myocardial perfusion, which is affected by coronary artery function (290). It needs to be determined whether fat accumulation in the liver induces myocardial insulin resistance via humoral mechanisms, as recently discussed (291), and/or mainly reflects myocardial steatosis and abnormal cardiac metabolism, parameters that strongly correlate with liver fat content (292).
It has not been determined whether fatty liver is mainly a result of insulin resistance of adipose tissue and skeletal muscle or whether fatty liver may also develop independent of the aforementioned conditions. Animal studies provided the first evidence that the latter could also be the case. Insulin resistance can be induced in vivo by overexpression of suppressor of cytokine signaling (SOCS)-1 or -3 in liver (293). SOCS proteins attenuate insulin signaling by binding to the insulin receptor and reducing its ability to phosphorylate IRS proteins (294, 295, 296). This hepatic overexpression of SOCS proteins is associated with an increase in SREBP-1c and hepatic steatosis (293). Conversely, suppression of SOCS-1, SOCS-3, or both in liver partially rescues impaired insulin sensitivity and ameliorates hyperinsulinemia in diabetic db/db mice. More importantly, suppression of SOCS proteins, especially SOCS-3, markedly improves hepatic steatosis. In summary, these findings suggest that fatty liver may also develop by alteration of hepatic insulin signaling and/or by direct effects of SOCS proteins on SREBP-1c in the liver (293, 297, 298). Thus, fatty liver may develop independent of skeletal muscle and adipose tissue insulin resistance.
Furthermore, there are human data showing that fatty liver may even have a primary role in the pathophysiology of skeletal muscle insulin resistance. In patients with type 2 diabetes, the PPARγ agonist rosiglitazone, as well as metformin, increases hepatic insulin sensitivity via activation of AMPK (299). However, a decrease in liver fat is only seen in subjects receiving thiazolidinediones. More importantly, insulin sensitivity of glucose disposal increases only in the thiazolidinedione group (300). Because skeletal muscle is not a major target of PPARγ action (301), these data support the notion that the increase in skeletal muscle insulin sensitivity in the thiazolidinedione group may be mediated by the decrease in liver fat.
A study by Hwang et al. (289), with quantification of fat in liver and skeletal muscle by 1H-MRS and measurement of visceral fat by MRT and of endogenous glucose production and insulin sensitivity of glucose disposal by tracer methods, further supports a role of hepatic fat accumulation in the pathophysiology of skeletal muscle insulin resistance. In that study, the negative correlation between liver fat content and skeletal muscle insulin sensitivity is exceptionally tight (289). The authors discuss the fact that their data, together with previous studies (302, 303, 304), suggest that the liver releases factors that regulate insulin sensitivity in skeletal muscle.
Fetuin-A [former name for the human protein, α2-Heremans-Schmid glycoprotein (AHSG)] may represent one of these factors. Fetuin-A is predominantly expressed in the liver, and to a lesser degree in the placenta and the tongue (305). Because placental expression is only relevant during pregnancy and the tongue is not an organ with endocrine activity, the liver is the only organ regulating circulating fetuin-A levels. This protein is a natural inhibitor of the insulin receptor tyrosine kinase in liver and skeletal muscle (306, 307, 308, 309, 310). Furthermore, mice deficient for the gene encoding fetuin-A display improved insulin signaling (311), suggesting that fetuin-A may play a major role in the regulation of insulin sensitivity in animals. In humans, SNPs in the fetuin-A gene (AHSG) are associated with type 2 diabetes (312). However, the role of this protein in the natural history of type 2 diabetes was unknown for a long time. Of note, severe liver damage as in cirrhosis, acute viral hepatitis, and cancer is associated with a decrease and not an increase in circulating fetuin-A (313). Thus, no liver dysfunction was known to be associated with elevated fetuin-A production in humans. Recently, fetuin-A mRNA expression was found to be increased in fatty liver in mice (281), which is in agreement with previous data from rats (314). In addition, circulating fetuin-A correlates positively with liver fat in humans in cross-sectional and longitudinal analyses. Circulating fetuin-A also correlates negatively with insulin sensitivity (281, 315). Moreover, high fetuin-A plasma levels predict change in insulin sensitivity, measured by the euglycemic, hyperinsulinemic clamp in prospective analyses (281) and are associated with incident type 2 diabetes (316, 317). In agreement with the notion that circulating fetuin-A is increased in fatty liver and insulin resistance, plasma fetuin-A is associated with the metabolic syndrome and correlates positively with CRP levels (316). Furthermore, fetuin-A promotes cytokine expression in monocytes and adipocytes and represses the production of the insulin-sensitizing adipokine adiponectin (317). Thus, these data support the hypothesis that fetuin-A may be one of the factors that mediate effects of fatty liver to other tissues. Such factors may be referred to as “hepatokines.”
Another protein that is preferentially produced by the liver is FGF21 (318). It has beneficial effects on lipid metabolism, as well as insulin sensitivity and pancreatic β-cell function (319, 320, 321). These effects of FGF21 on metabolism in animal models are not accompanied by changes in body weight (319). This finding is interesting because a profound synergy between the effects of FGF21 and the thiazolidinedione rosiglitazone, which induces weight gain, exists in stimulating glucose uptake in 3T3-L1 adipocytes (322). In addition, FGF21 regulates hepatic steatosis. FGF21 expression in the liver in the fasted state is induced by PPARα. Accordingly, FGF21 expression in the livers of fasted mice is absent in PPARα-deficient animals. These animals have fatty liver and serum hypertriglyceridemia (323, 324, 325, 326). Furthermore, a decrease in endogenous FGF21 expression by RNA interference induces fatty liver and hyperlipidemia (323). So far, there is little information on the relationship of FGF21 with metabolic traits in humans. In a cross-sectional study in 200 subjects, circulating FGF21 levels correlated positively with components of the metabolic syndrome, but not with insulin sensitivity estimated from fasting serum glucose and insulin levels, independent of obesity (327). Whether hepatic FGF21 expression and production are affected by hepatic steatosis needs to be investigated.
Another very interesting protein, retinol binding protein 4 (RBP4), is expressed in adipose tissue and in the liver and is secreted into circulation (328). The first evidence that RBP4 has major effects on metabolism was found in adipose-specific knockout of glucose transporter 4 mice (329) that display insulin resistance in skeletal muscle, liver, and adipose tissue (330). In these animals, expression of Rbp4 in adipose tissue and serum RBP4 levels are increased. In addition, increase in serum RBP4 concentrations by transgenic overexpression or by injection of purified RBP4 protein into wild-type mice causes insulin resistance (329). Furthermore, Rbp4 knockout mice display enhanced insulin sensitivity, and lowering of serum RBP4 with the synthetic retinoid fenretinide improves insulin sensitivity and glucose tolerance in mice on a high-fat diet (329). Moreover, in humans high circulating RBP4 is associated with insulin resistance in cross-sectional studies (331, 332, 333, 334, 335, 336). In addition, a strong relationship between changes in circulating RBP4 and insulin sensitivity is shown in longitudinal studies (331, 333). Recent data suggest that the elevated circulating RBP4 in insulin-resistant states is a result of increased production from the increased visceral fat mass (332), as well as fatty liver (333).
Altogether, there is strong support to show that fatty liver produces humoral factors affecting insulin signaling in insulin-responsive tissues. Thus, further efforts are warranted to identify these hepatokines.
D. Dissociation of fatty liver and insulin resistance
Although hepatic fat accumulation, both in animals and in humans, is strongly associated with a decrease in insulin sensitivity, a large variability in this relationship exists that cannot be explained by other parameters regulating insulin sensitivity such as overall obesity, body fat distribution, or circulating adipokines. In other words, for the same amount of hepatic steatosis, subjects can be identified who have very high and very low insulin resistance (Fig. 4⇓), suggesting that a dissociation of fatty liver and insulin resistance exists. The paradox of this finding may be due to lipotoxicity. This term was mainly devised by Roger Unger to describe the deleterious effects of lipid accumulation in various tissues (75, 337). According to this concept, triglycerides are probably the least toxic form in which the lipid excess can be stored in ectopic tissues, at least in the short term. The incorporation of fatty acids into triglycerides, as well as their oxidative degradation, thus represents protection from lipotoxicity. However, when these compensatory mechanisms are overwhelmed, fatty acids induce damage to cells resulting in impaired metabolism (75, 249, 337, 338) (Fig. 5⇓).
Fig. 4.
Variability in the relationship between liver fat and insulin sensitivity in humans. This image depicts the strong, negative relationship between liver fat measured by 1H-MRS and insulin sensitivity measured by the euglycemic- hyperinsulinemic clamp in 200 individuals without type 2 diabetes (regression line and 95% confidence interval). For a very similar amount of liver fat, individuals can be identified who are relatively insulin sensitive (upper circle) and insulin resistant (lower circle). Major determinants of insulin sensitivity such as age, gender, total and visceral body fat mass measured by MRT, and intramyocellular fat in the tibialis anterior muscle, measured by 1H-MRS, cannot explain this difference in insulin sensitivity.
Fig. 5.
Metabolic consequences of fatty liver. Fat accumulation in the liver induces hyperglycemia, subclinical inflammation dyslipidemia, and the secretion of parameters that can be referred to as “hepatokines” (e.g., fetuin-A), thereby inducing insulin resistance, atherosclerosis, and possibly β-cell dysfunction and apoptosis. The degree of these conditions may be moderate [benign fatty liver (left panel)]. However, the same amount of hepatic fat accumulation may, by mechanisms that are yet not fully understood, be strongly associated with hepatic lipotoxicity, resulting in aggravation of hyperglycemia, subclinical inflammation, dyslipidemia, and an imbalance in hepatokine production as well as in their metabolic consequences. This state may be referred to as malign fatty liver (right panel).
Several pathways are thought to be operative in this process. Among them, activation of NF-κB and JNK pathways, as well as the Janus kinase-signal transducer and activator of transcription-3-SOCS-3 pathway, which are involved in insulin resistance (47, 223, 339), is critical. Cai et al. (59) elegantly showed that NF-κB transcriptional targets are activated in liver by obesity and a high-fat diet. This is associated with a chronic state of subacute inflammation and insulin resistance. Inhibition of NF-κB activation under a high-fat diet still results in hepatic steatosis; however, this intervention is not accompanied by insulin resistance (59). These findings indicate that fat accumulation in the liver leads to subacute hepatic inflammation through NF-κB activation. In addition, under conditions of inhibited NF-κB stimulation, fatty liver does not result in insulin resistance. In support of this hypothesis, liver-specific inactivation of the NF-κB essential modulator gene in mice under a high-fat diet results in hepatic steatosis, but not in insulin resistance (340). The susceptibility to inflammatory responses may modulate the dissociation of fatty liver and insulin resistance. In this aspect, carriers of the −1031C and −863A variants of the SNPs in the promoter region of the TNF-α gene (TNF) have high serum levels of the soluble TNF receptor 2, indicating elevated TNF-α production. Furthermore, they are insulin resistant and have steatohepatitis more frequently than simple steatosis (341). Similar results for other SNPs in TNF are reported elsewhere (342).
Another interesting animal model for the dissociation of fatty liver and insulin resistance is the liver-specific acyl:CoA:diacylglycerol acyltransferase 2 (DGAT2) transgene mouse (343). DGAT enzymes, among them particularly DGAT2, catalyze the final step of triacylglycerol biosynthesis (344). Liver-specific DGAT2 overexpressing mice develop hepatic steatosis with a 5-fold increase in liver triglyceride content compared with controls. However, this condition is not accompanied by whole-body or hepatic insulin resistance. In agreement with these novel findings, antisense oligonucleotide treatment targeting the DGAT2 gene reduces liver triglycerides in mice fed a high-fat diet, without improving insulin sensitivity or glucose tolerance (345). In another study, DGAT2 silencing also reduced hepatic steatosis, while insulin sensitivity improved as well. This finding, however, may be attributable to an effect of DGAT2 silencing on decreasing body weight and epididymal fat pad mass (346). The mechanism for the dissociation of fatty liver and insulin resistance in this animal model is not fully understood. It may be that an increase in triglyceride synthesis protects from fatty acid-induced lipotoxicity. This hypothesis is supported by the finding that on a high-fat diet, activation of JNK and NF-κB in DGAT2 transgenic mice is not increased compared with controls. Alternatively, the increase in unsaturated fatty acids, which are found in the tissue of these animals and are considered to be less lipotoxic compared with saturated fatty acids, may generate the phenotype.
Support for the involvement of the fatty acid pattern in the dissociation of fatty liver and insulin resistance is provided by another recently described animal model. Mice deficient for the elongation of long-chain fatty acids (ELOVL) gene (Elovl6) develop obesity and hepatic steatosis, but not insulin resistance, hyperinsulinemia, or hyperglycemia under a high-fat diet (339). Elovl6 encodes for the enzyme ELOVL, catalyzing the conversion of palmitate (C 16:0) to stearate (C 18:0) as well as palmitoleate (C 16:1n-7) to vaccinate (C 18:1n-7), thus regulating the tissue fatty acid composition (347, 348). Interestingly, amelioration of hepatic insulin resistance in these animals cannot be explained by changes in energy balance or proinflammatory signals. However, a suppression of elongation and degradation of fatty acids, resulting in moderately increased hepatic triglyceride content, as well as a decrease in the diacylglycerol-protein kinase Cε pathway occurs (339). This observation is important because hepatic protein kinase Cε is involved in the development of hepatic insulin resistance (349). Although these animal data provide novel and mechanistic evidence for the existence of a dissociation of fatty liver and insulin resistance, human studies have not specifically addressed this interesting point. Based on the aforementioned findings in animals, we studied the relationship of a SNP in DGAT2, which is associated with obesity (350), with liver fat and insulin resistance in humans. In 200 subjects, the SNP in DGAT2 is associated with changes in liver fat, but not insulin sensitivity during a lifestyle intervention (our184), supporting the hypothesis that DGAT2 may differentially affect liver fat and insulin sensitivity in humans, too.
V. Concluding Remarks
Although the roles of adipose tissue, and particularly VAT, in the pathophysiology of metabolic diseases such as type 2 diabetes, the metabolic syndrome, and atherosclerosis have been carefully studied, the impact of fatty liver in the natural history of these diseases has long been underestimated. With increasing evidence from transgenic and knockout animal models that hepatic steatosis is involved in several major pathways regulating glucose and lipid metabolism, fatty liver gained recognition in the metabolic field of research. This effect was accompanied by the identification of exciting novel targets to prevent and treat hepatic fat accumulation. Moreover, there is strong support indicating that different aspects of fatty liver exist and are associated with severe or merely moderate metabolic disturbances. Finally, similar to adipose tissue, liver under conditions of an increased lipid load may have important secretory functions, and in analogy to adipokines, hepatokines may become an interesting target for future research.
From a clinical aspect, prevention of ectopic fat deposition in liver, as well as in other insulin-sensitive tissues under conditions of a sedentary lifestyle, overnutrition, and disproportionate adipose tissue distribution, is the primary goal in the protection from obesity-induced insulin resistance. When such efforts are not very effective, targeting lipotoxicity, which appears to be the predominant mediator of metabolic consequences of fatty liver, seems to be an effective strategy to accomplish this mission.
Acknowledgments
We thank our colleagues in the Medical Department and the Department of Experimental Radiology at the University of Tübingen, as well as the Deutsche Forschungsgemeinschaft for their support.
Footnotes
- This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (KFO 114). N.S. is currently supported by a Heisenberg Grant of the Deutsche Forschungsgemeinschaft.
- Disclosure Statement: The authors have nothing to disclose.
- First Published Online August 21, 2008
- Abbreviations: ADIPOR1, Adiponectin receptor-1; AMPK, AMP-activated protein kinase; BMI, body mass index; ChREBP, carbohydrate response element-binding protein; CLOCK, circadian locomotor output cycles protein kaput; CoA, coenzyme A; CRP, C-reactive protein; CT, computed tomographic; CYP7A1, cytochrome P450 cholesterol 7a-hydroxylase; D2, type 2 iodothyronine deiodinase; DGAT2, diacylglycerol acyltransferase 2; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FACoA, fatty acyl CoA; FFA, free fatty acid; FGF, fibroblast growth factor; FXR, farnesoid X receptor; HDL, high-density lipoprotein; 1H-MRS, proton magnetic resonance spectroscopy; IFN, interferon; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LDL, low-density-lipoprotein; LXR, liver X receptor; MR, magnetic resonance; MTP, microsomal transfer protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor κB; NK, natural killer; PGC-1α, PPARγ coactivator 1α; PPAR, peroxisome proliferator-activated receptor; RBP4, retinol binding protein 4; ROS, reactive oxygen species; SNP, single nucleotide polymorphism; SOCS, suppressor of cytokine signaling; SREBP-1c, sterol-regulatory binding protein 1c; VAT, visceral adipose tissue; VLDL, very low-density lipoprotein.
- Received February 13, 2008.
- Accepted August 11, 2008.
