Determinants of ectopic liver fat in metabolic disease

Abstract

Common obesity-associated hepatic steatosis (nonalcoholic fatty liver disease (NAFLD)) and insulin resistance are mainly caused by dysfunctional adipose tissue. This adipose tissue dysfunction leads to increased delivery of NEFA and glycerol to the liver that (i) drives hepatic gluconeogenesis and (ii) facilitates the accumulation of lipids and insulin signaling inhibiting lipid intermediates. Dysfunctional adipose tissue can be caused by impaired lipid storage (overflow hypothesis, characterized by large visceral adipocytes) or increased lipolysis (due to impaired postprandial suppression of lipolysis in inflamed, insulin-resistant adipocytes). In line with the adipose tissue expandability hypothesis the amount and distribution of adipose tissue correlate with its dysfunction and thus with liver fat. This relationship is however modified by endocrine effects on lipid storage and lipolysis as well as dietary effects on hepatic lipogenesis and lipid oxidation. The association between body composition characteristics like visceral obesity or fat cell size and ectopic liver fat is modified by these influences. Phenotyping obesity according to metabolic risk should integrate body composition characteristics, endocrine parameters and information on diet.

Introduction

As a consequence of an unhealthy lifestyle, nonalcoholic fatty liver disease (NAFLD, defined as accumulation of fatty acid content greater than 5% of liver weight) reaches a prevalence of 17–30% and is becoming the most common cause of chronic liver disease in Western countries [1]. Hepatic steatosis is the key feature of metabolically unhealthy obesity because it is most closely related to insulin resistance in liver, muscle and adipose tissue irrespective of the amount of visceral adipose tissue [2]. Weight loss in obese subjects leads to immediate improvement in hepatic insulin sensitivity that precedes changes in peripheral insulin sensitivity and is associated with an early decrease in liver fat [3,4,5]. Further evidence for a causal relationship between liver fat and hepatic insulin resistance comes from leptin treatment in lipodystrophic humans that reversed hepatic steatosis and insulin resistance [6].

The presence of hepatic steatosis is however not always related to metabolic disturbances. Genetic variants that are accompanied by a higher liver fat content (patatin-like phospholipase domain containing three protein (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2)) do not exhibit insulin resistance or features of the metabolic syndrome (for a review see ref. [7]). In addition, the dose–response relationship between liver fat and insulin resistance is not convincing because the presence of low amounts of liver fat was already associated with a maximal impairment of hepatic, adipose tissue and peripheral insulin resistance in obese subjects [8]. These authors also found that intrahepatic triglycerides were not essential for hepatic insulin resistance [8]. Instead, hepatic cytosolic diacylglycerol content, a synthetic precursor of triglycerides and a signaling molecule, was associated with hepatic protein kinase ε activation and impaired insulin signaling [8, 9]. However, besides the direct inhibition of hepatic insulin signaling by diacylglycerols, impaired insulin signaling in adipose tissue indirectly impairs hepatic insulin sensitivity by increasing delivery of nonesterified fatty acid (NEFA) and glycerol to the liver and thus driving hepatic gluconeogenesis [10].

This review discusses the multifactorial causes of increased liver fat in obesity that includes impaired lipid storage and increased lipolysis in adipose tissue as well as increased hepatic de novo lipogenesis and lipid retention due to impaired apolipoprotein secretion or beta-oxidation (Fig. 1).

Fig. 1
figure1

Pathogenesis of liver fat accumulation includes: (1) a greater delivery of nonesterified fatty acids (NEFAs) to the liver from adipose tissue lipolysis; (2) increased delivery of dietary fatty acids to the liver; (3) increased hepatic de novo lipogenesis (DNL); (4) impaired fatty acid oxidation; and (5) reduced VLDL-TG production and secretion

Adipose tissue dysfunction

Subcutaneous adipose tissue can be seen as a metabolic sink for clearance of extra calories. Lipids are thus safely stored and prevented from ‘spilling over’ into the lean tissue compartment like liver, heart, muscle and pancreas where this ectopic fat can cause metabolic disturbances. According to the lipid overflow or adipose tissue expandability hypothesis, postprandial lipid storage in adipose tissue is impaired in metabolically unhealthy obesity. In the postprandial period, about 70% of chylomicron triglycerides are hydrolyzed by capillary lipoprotein lipase in extrahepatic tissues, such as adipose tissue, leaving chylomicron remnants to be taken up by the liver [11]. A proportion of fatty acids liberated by the action of lipoprotein lipase that is not taken up by subcutaneous adipose tissue were shown to ‘spillover’ into the systemic NEFA pool [12, 13]. In line with the importance of lipid storage capacity, the drugs thiazolidinediones exert their antidiabetic effects by improving adiopogenesis and thus lipid storage in adipose tissue [14]. Limited lipid storage capacity is characterized by adipocyte hypertrophy, hypoxia and accumulation of proinflammatory cells, including M1 macrophages, mast cells and various T-lymphocyte classes, which contributes to insulin resistance [15]. In particular, visceral adipose tissue is prone to inflammatory infiltration and is therefore secreting large quantities of proinflammatory, pro-atherogenic cytokines and free fatty acids [16]. In addition, visceral fat may be more harmful than excess subcutaneous fat because lipolysis of visceral adipocytes releases free fatty acids (FFAs) into the portal vein, directly to the liver. The comparison of portal and systemic fatty acid kinetics has shown that the contribution of FFAs derived from visceral fat mass to the portal and systemic circulations increases with increasing visceral fat (5% in lean and 20% in obese subjects, see ref. [17]). However, the highest amount of FFAs delivered to the liver originates from lipolysis in subcutaneous adipose tissue (95% in lean and 80% in obese subjects) that reach the liver mainly via the portal circulation (about 80% of hepatic blood flow) and to a minor part via the hepatic artery (20% of hepatic blood flow). In addition, the increased release of FFA from visceral fat is unlikely to be responsible for ectopic lipid accumulation and insulin resistance in skeletal muscle because it contributes to only a small proportion of total FFAs delivered to skeletal muscle, even in obese subjects [17]. Accordingly, comparison of correlation coefficients between body fat distribution (visceral and subcutaneous fat) and insulin-mediated glucose uptake [18] or metabolic risk factors [19, 20] did not reveal a clear advantage or only showed a small benefit of visceral over subcutaneous fat.

In line with the hypothesis that it is subcutaneous adipose tissue dysfunction that contributes to the redistribution of energy surplus to ectopic lipids, 56-day overfeeding of non-obese volunteers let to altered gene regulation in subcutaneous adipose tissue that indicated impaired lipid storage and increased postprandial fatty acid spillover of ingested lipids [21]. The authors have also shown that the altered gene regulation in subcutaneous adipose tissue correlated with an accumulation of visceral fat. The increase in visceral adipose tissue may therefore be a marker of deleterious subcutaneous adipose tissue dysfunction rather than a major cause of metabolic dysfunction.

Although the limited expansion of subcutaneous adipose tissue during weight gain provides an attractive explanation for ectopic lipid accumulation, another 8-week overfeeding study in lean volunteers that tested the 'adipose expandability' hypothesis found no correlation between adipocyte size and ectopic liver fat accumulation [22]. Quite the contrary, subjects with smaller adipocytes experienced the worst overfeeding-induced impairment of clamp-derived whole-body insulin sensitivity and upregulated skeletal muscle inflammation. Interestingly, smaller adipocytes are associated with a higher lipolysis, whereas larger adipocytes in obesity are associated with reduced lipolysis [23]. These results suggest an important role of increased lipolysis rather than impaired postprandial lipid storage to ectopic lipid accumulation and metabolic impairment. There was however no association between lipid content of adipose tissue (a proxy for adipocyte size that is determined as fat mass /total adipose tissue-ratio) and liver fat in a cross-sectional study in adults [24]. This result may be due to the equal importance of impaired lipid storage (characterized by adipocyte hypertrophy) or higher lipolysis (associated with smaller adipocytes) for ectopic fat accumulation. In addition, although higher lipolysis is associated with smaller adipocytes and thus a lower lipid content of adipose tissue, adipocyte size alone is likely insufficient to explain ectopic lipid accumulation because the amount of adipose tissue is also important for the level of FFAs in the circulation. Increased FFA levels in obesity thus occur despite hypertrophic adipocytes because the downregulation of lipolysis in these adipocytes is unable to completely compensate for the increase in fat mass [23].

The importance of excessive lipolysis for hepatic fat accumulation is demonstrated by the finding that prolonged fasting for 24–48 h led to an increase in intrahepatocellular lipids in men [25, 26]. Furthermore, acute bouts of aerobic exercise induce lipolysis and thus lead to an immediate increase in liver fat [27], whereas chronic aerobic and resistance exercise for 8–48 weeks (3–7 d per week, 45–75% of VO2max) is successful in mobilizing liver fat, independent of weight loss [28].

Interestingly, the interindividual variance in hepatic lipid accumulation during prolonged fasting was high [25, 26]. It was suggested that an increase in intrahepatocellular lipids reflects a maladaptive response to increased FFA delivery to the liver that unmasks a subtle defect in mitochondrial function [29]. NAFLD was indeed associated with impaired hepatic mitochondrial function assessed by the 13C-ketoisocaproate breath test [30].

Endocrine determinants of intrahepatocellular lipids

Free triiodothyronine (fT3) levels were found to be positively associated with NAFLD in euthyroid middle-aged subjects [31, 32]. In obesity, increased serum thyroid-stimulating hormone and fT3 occur partly due to increased leptin levels (for review see ref. [33]). The impact of fT3 on hepatic steatosis could be explained by an enhanced thyroid hormone-mediated (i) hepatic lipogenesis [34] and (ii) increase of epinephrine-induced lipolysis in subcutaneous adipose tissue [35]. Recent metabolic profiling also confirmed the lipolytic and lipogenic effects of thyroid hormones even within the physiological range [36]. Thyroid hormones might also be important in regulating hepatic FFA uptake because hyperthyroidism increases triglyceride-derived fatty acid uptake in oxidative tissues such as liver, whereas hypothyroidism increases triglyceride-derived fatty acid uptake in white adipose tissue and decreases its uptake in liver [37]. During hyperthyroidism, there is however a net reduction in total hepatic triglycerides [38] due to a higher rate of fatty acid metabolism when compared with fatty acid synthesis. In this occasion, thyroid hormones increase the activity of hepatic lipases, lipophagy and mitochondrial fatty acid oxidation [39], which are the primary processes used by the liver to reduce steatosis [40]. The correlation between fT3 levels and hepatocellular lipids may therefore reflect a maladaptive response to increased thyroid hormone-induced lipolysis and de novo lipogenesis in the liver that unmasks a subtle defect in mitochondrial function. Hepatic mitochondria have indeed been found to be structurally and molecularly altered in NAFLD [41] and impaired hepatic mitochondrial function assessed by the 13C-ketoisocaproate breath test was found in these patients [30]. A decline in mitochondrial function may not only provoke metabolic disturbances but even contribute to NAFLD progression [42].

In insulin-resistant states, elevated secretion of catecholamines and glucagon can stimulate lipolysis and may thus contribute to hepatic steatosis. The effect of insulin on ectopic liver fat is discussed below in the context of carbohydrate intake and glycemic index. The association of adipokines with the development and progression of NAFLD is complex and lies beyond the scope of this review and was discussed recently [43].

Dietary determinants of intrahepatocellular lipids

Results of human intervention studies have clearly shown that a hypercaloric diet, regardless of whether the excess calories were provided either as fat, sugar or both, increases liver fat content [7]. Weight loss and physical activity remain the prevalent lifestyle strategies for prevention and treatment of NAFLD [44]. However, beyond energy balance, isocaloric feeding studies provide evidence that diet composition affects hepatic fat accumulation.

Because dietary fatty acids can enter the liver as either chylomicron remnants or 'spillover'-derived NEFA hydrolyzed from chylomicrons and not taken up by peripheral tissues, dietary fat intake leads to an immediate postprandial increase in liver fat between 3 and 6 h postprandially [45,46,47] as well as an increase in hepatic, adipose tissue and whole-body insulin resistance [47]. A habitual high-fat diet could therefore contribute to ectopic liver fat accumulation and adipose tissue dysfunction independent of a chronic positive energy balance. This is supported by human intervention studies that compared short-term isocaloric, high-fat versus low-fat feeding that have shown that low-fat diets reduce liver fat content, whereas isocaloric high-fat diets increase liver fat content (for review see ref. [7]).

In addition to fat intake, fatty acid composition of the diet may play an important role for liver fat accumulation. In a cross-sectional study, consumption of greater amounts of dairy fat was associated with lower fasting glucose concentrations, better glucose tolerance, higher systemic and hepatic insulin sensitivity and less liver fat [48]. As the underlying mechanism it was proposed that trans-palmitoleic acid (trans-16:1n−7), phytanic and possibly other dairy fatty acids may stimulate hepatic β-oxidation and/or inhibit de novo lipogenesis (DNL). Intake of mono-unsaturated fatty acids (MUFAs) may also protect from hepatic steatosis. Twelve weeks of isocaloric supplemention with olive oil (28% of total energy intake with MUFA) reduced liver fat fraction by approximately 17% and improved hepatic and peripheral insulin sensitivity in prediabetic people without a change in body weight or physical activity [49]. In line with these findings, an isocaloric diet enriched in MUFA lowered liver fat content in patients with prediabetes and type 2 diabetes by increasing fat oxidation [50, 51]. As underlying mechanisms, MUFAs may increase fat oxidation and inhibit lipogenesis or promote fat storage in adipose tissue by increasing lipoprotein lipase activity (for a review see ref. [52]). By contrast, the controlled isocaloric substitution of carbohydrates [53] or poly-unsaturated fatty acids (PUFAs) [54] by saturated fatty acids (SFAs) let to an increase in hepatic and visceral fat in healthy subjects. As an underlying mechanism, SFAs might induce lipogenesis, whereas PUFA may stimulate fat oxidation and inhibit de novo lipogenesis (for review see ref. [52]). Moreover, the availability of n-3 long chain PUFAs can play a role in regulation of liver fat content [55].

Ingestion of excess dietary carbohydrates can lead to increased substrate availability for DNL and thus increase liver fat. DNL plays an important role for liver fat content because approximately 60% of liver triglycerides are derived from NEFA influx from adipose tissue, 26% from de novo lipogenesis, and 15% from the diet [11]. Other data show that the contribution of DNL to the total very low-density lipoprotein-triglyceride (VLDL-TG) pool varies between 10 and 35% [56] and is higher in overweight and NAFLD compared to lean insulin-sensitive subjects [57, 58]. This may in part be due to the fact that stimulation of DNL remains insulin sensitive in insulin-resistant individuals [59]. Mechanisms that explain increased hepatic DNL are the activation of the transcription factors Sterol Response Element Binding Protein 1c (SREBP-1c) and Carbohydrate Response Element Binding Protein (ChREBP). ChREBP is stimulated by glucose and regulates DNL in adipocytes, whereas insulin stimulates lipogenesis through SREBP in the liver (for a review see ref. [60]). Consumption of high-glycemic index foods or a high-glycemic load diet could therefore contribute to hepatic steatosis by increasing postprandial insulin secretion. After weight loss, hypercaloric refeeding of a high-glycemic load diet indeed led to an increase in liver fat that was prevented by a low-glycemic load diet despite a higher fat content [61]. In epidemiological studies, sugar-sweetened beverage intake was positively associated with NAFLD [62, 63]. The consumption of dietary carbohydrates and especially rice was associated with NAFLD in Japanese women [64].

Despite a low insulin response, fructose has a high potential to increase DNL. The isocaloric substitution of dietary fructose for ‘complex carbohydrates’ (cereals, bread, pasta, rice and potatoes) thus led to increased liver fat content that was associated with increased postprandial hepatic DNL, and reduced whole-body fatty acid oxidation [65]. By contrast, other studies found no influence of an isocaloric increase in sugar consumption on liver fat content [66,67,68], suggesting that energy overconsumption is a prerequisite of liver fat accumulation.

In summary, a Western dietary pattern with a high-glycemic load, fructose consumption, saturated fat and cholesterol intake can contribute to hepatic steatosis through effects on hepatic de novo lipogenesis and lipid oxidation that may aggravate the negative impact of energy overconsumption [52].

Hepatic lipid export

Increased VLDL-TG secretion from non-systemic sources was found in NAFLD and is presumably derived primarily from lipolysis of intrahepatic and visceral fat and de novo lipogenesis [69]. Hepatic lipid export increased with liver fat content up to 10% liver fat but was unable to compensate the increased lipid load.

In conclusion, the development of NAFLD is determined by adipose tissue function rather than mass, along with dietary or lifestyle factors. Understanding the multiple factors that influence hepatic lipid accumulation could help to explain the discrepancies between obesity and metabolic risk (e.g., in metabolically healthy obese or metabolically unhealthy lean phenotypes).

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Correspondence to Anja Bosy-Westphal.

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Bosy-Westphal, A., Braun, W., Albrecht, V. et al. Determinants of ectopic liver fat in metabolic disease. Eur J Clin Nutr 73, 209–214 (2019). https://doi.org/10.1038/s41430-018-0323-7

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