Non-alcohol fatty liver disease (NAFLD) är relaterad till insulinresistens och typ 2-diabetes och hjärtkärlsjukdom. Hörnstenen i behandlingen av NAFLD är viktminskning och ökad fysisk aktivitet för förbättrad insulinkänslighet (1).
Även om energiintagsrestriktion är den primära behandlingen är det intressant att studera effekter av enskilda makronutrienter på fettinnehållet (intrahepatisk triglycerider, IHTG) i levern.
I en nypublicerad studie jämförde Luukkonen et al effekter av tre olika dieter på bland annat IHTG (2). 38 kvinnor och män (48±2 år, BMI: 31±1 kg/m2) delades in i tre grupper som vardera under tre veckor fick 1000 kcal extra per dag i form av livsmedel med antingen hög halt av mättat fett, omättat fett eller enkla kolhydrater.
De tre grupperna ökade lika mycket i vikt, 1,4±1,5%. I gruppen som åt mättat fett ökade IHTG med 55% (4,9±6,6 vs. 7,6±8,8%, P <0,001), i gruppen som åt omättat fett var ökningen 15% (4,8± vs. 5,5±4,8%, P <0,02) och i kolhydratgruppen ökade IHTG 33% (4,3±4,7 vs. 5,7±5,4%, P <0,02).
Ökningen var större för de som åt ett energiöverskott som mättat fett jämfört med omättat fett (P <0,01). Skillnaderna var oberoende ökningen i kroppsvikt. De novo lipogenes (DNL) i levern ökade signifikant i kolhydratgruppen men inte för de två andra dietgrupperna. Fastande S-insulin ökade signifikant i gruppen som åt mättat fett men var oförändrade i de två andra dietgrupperna. Serum-nivåer av fria fettsyror som avspeglar nettoeffekten av lipolys och lipogenes var oförändrade i gruppen som åt mättat fett men sjönk i de två andra dietgrupperna.
Sammanfattning och tolkningar av resultatet
Den experimentella studien av Luukkonen et al ger ytterligare underlag och mekanistiska förklaringar till varför fettkvaliteten i kosten är viktig och kan påverka leverns fettinnehåll oberoende energiintag.
Resultaten är i linje med aktuella nordiska och internationella riktlinjer för hälsosamma matvanor för befolkningen som säger att vi bland annat ska begränsa intaget av livsmedel med mättat fett respektive socker och äta mer av vegetabiliska fetter, (fet) fisk samt nötter och frön.
1. McCarthy EM, Rinella ME. The role of diet and nutrient composition in nonalcoholic fatty liver disease. J Acad Nutr Diet 2012;112:401-409.
2. Luukkonen PK, Sädevirta S, Zhou Y et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat oro simple sugars. Diabetes Care 2018 https://doi.org/10.2337/dc18-0071.
Referat för DiabetologNytt
Ingrid Larsson, klinisk näringsfysiolog, docent, Enheten för Klinisk nutrition och Regionalt Obesitascentrum, SU Sahlgrenska, Göteborg
www red DiabetologNytt
Hannele Yki-Järvinen sista författar-namn
Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars, Diab Care May 29, 2018
Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content),predisposes to type 2diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition inﬂuences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.
RESEARCH DESIGN AND METHODS
We overfed 38 overweight subjects (age 48 6 2, BMI 31 6 1 kg/m2, liver fat 4.7 6
0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia, insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.
Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT signiﬁcantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and signiﬁcantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.
Macronutrient composition of excess energy inﬂuences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneﬁcial in reducing IHTG and the associated risk of diabetes.
From the article
NAFLD has been shown to predict type 2 diabetes and cardiovascular disease in multiple studies, even independent of obesity (1), and also to increase the risk of progressive liver disease (17). It is therefore interesting to compare effects of different diets on liver fat content and understand the underlying mechanisms. We examinedwhetherprovisionofexcess calories as saturated (SAT) or unsaturated (UNSAT) fats or simple sugars (CARB) inﬂuences the metabolic response to overfeeding in overweight subjects. All overfeeding diets increased IHTGs. The SAT diet induced a greater increase in IHTGs than the UNSAT diet. The compo-sition of the diet altered sources of excess IHTGs. The SAT diet increased lipolysis, whereas the CARB diet stimulated DNL. TheSATbutnottheotherdietsincreased multiple plasma ceramides, which in-crease the risk of cardiovascular disease independent of LDL cholesterol (18).
The FA composition of liver TG is similar to that in VLDL (4). We monitored com-pliance by analyzing changes in FA com-position of VLDL-TG. The SAT diet increased SFA, and the UNSAT diet in-creased PUFA (Fig. 1B). The CARB diet also increased SFAs, which are exclusive products of DNL (5). These data demonstrate that subjects were compliant and are novel in showing that different diets have distinct effects on hepatic FA com-position as determined from that in VLDL-TG. Weight gain averaged 1.2 kg in all subjects overeating 1,000 kcal for 3 weeks. This weight gain is consistent with the gain of 1.6 kg observed by Ris´erus and colleagues (2) in healthy subjects over-eating 600 kcal/day for 7 weeks but less than the gain of 2.3 kg observed by Harris et al. (19) during the ﬁrst 3 weeks of overfeeding 1,000 kcal/day. As in the current study, interindividual variation in the latter study was large and ranged from 1 to 7 kg after 8 weeks (19). We also observed slight but not signiﬁcantly less weight gain in subjects fed the UNSAT diet comparedwiththeotherdiets.However, the important key ﬁndings (i.e., the greater increase in liver fat, lipolysis, and ceramides by the SAT compared with the UNSAT diet) were independent of changes in body weight.
Overfeeding increases IHTG (2,5,20). The SAT diet increased IHTG signiﬁcantly more than the UNSAT diet in the face ofsimilarenergyexcessandindependent of changes in body weight. This is con-sistent with a previous study showing a greater increase in IHTG after overfeed-ing saturated than polyunsaturated fat (2). Similarly, an isocaloric saturated fat-enriched diet increases IHTG compared with polyunsaturated fat (21). High sat-urated fat intakes characterize subjects with NAFLD (22,23). Thus, diet compo-sition inﬂuences IHTG, and saturated fat induces a greater accumulation of IHTG than unsaturated fat.
Pathways of IHTG
Regarding the mechanisms underlying increased IHTG during overfeeding, di-rect quantiﬁcation of sources of FAs in IHTG using stable isotopes and liver biopsy specimens in subjects with elevated IHTG has shown that most IHTGs are derived from adipose tissue lipolysis (59%) and DNL (26%) (4). We found SAT increased and UNSAT decreased adipose tissue li-polysis. Lipolysis was traced using deu-terated glycerol, which is not reesteriﬁed in adipose tissue due to a lack of glycerol kinase. This contrasts with serum FFA, which concentration reﬂects net effects of lipolysis and lipogenesis. Overfeeding de-creasedserumFFA,asreportedpreviously (20). No studies have measured overfeed-ing effects on lipolysis in humans. High-saturated fat–feeding in mice stimulates lipolysisviainﬂammatorymediators(6).In keeping with such data, we found upre-gulationofmultiple inﬂammation-related pathways in the adipose tissue transcrip-tome. PUFAs can inhibit lipolysis by acti-vation of G-protein coupled receptor 120, which mediates anti-inﬂammatory and insulin-sensitizingeffects (24,25). The opposite effects of the SAT and UNSAT diets on lipolysis, the major contributor to IHTG, could explain why the SAT diet increased IHTG to a greater extent than the UNSAT diet.
Overfeeding simple sugars stimulates DNL, which produces exclusively SFA in humansandoccursmainlyintheliver(5). Consistent with these data, the CARB diet increased hepatic DNL and SFAs in VLDL-TG (Figs. 1B and 2A). The CARB diet also induced multiple pathways related to carbohydrate metabolism in the adipose tissue transcriptome (Fig. 2D).
IR and Its Mediators
The SAT diet induced IR. This is consis-tent with several studies showing that isocaloric substitution of saturated for monounsaturated(26,27) or polyunsat-urated fat (28) or carbohydrates (27) ameliorates IR. A large prospective study recently reported intake of foods rich in SFA, such as butter and cheese, increased the risk of type 2 diabetes (29).
SAT but not the other diets increased multiple plasma ceramides. TGs themselves are inert and do not confer IR (7). Ceramides are key mediators of saturated fat-induced IR (8–10,30–33) in mice and are the most upregulated lipid species in inﬂamed adipose tissue in human NAFLD (34). SFAs and ceramides originating from de novo ceramide synthesis cosegregate with IR in human NAFLD (7). Saturated palmitoyl-CoA is an obligate precursor for the de novo pathway (8,30). The SAT diet thus may have induced IR via stimulating the de novo ceramide synthetic pathway in the liver. The SAT but not the other diets also increased markers of endotoxemia and upregulated genes related to gram-negative bacterial infection in adipose tissue.Thesechangescouldhavecontrib-uted to SAT-induced lipolysis and de novo ceramide synthesis, because in mice, en-dotoxin induces both adipose tissue in-ﬂammation (11) and ceramide-dependent IR (10).
Limitations of our study include small sample size although largest of its kind (35).Another limitation is that we did not assess physical activity objectively during the study. Including a control group being overfed their habitual diet might also have been helpful.
In conclusion, overfeeding saturated or unsaturated fat or simple sugars for 3 weeks increases IHTG, but its magnitude and the associated metabolic changes depend on the diet. Saturated fat induced the highest increase in IHTG by stimulating adipose tissue lipolysis, the major pathway of IHTG.
Moreover, saturated fat induced IR and increased circulating concentrations of ceramides. In contrast to saturated fat, overfeeding of unsaturated fat led to a smaller in-crease in IHTG, decreased lipolysis, and no change in ceramides. Simple sugars increased IHTG by stimulating DNL. Consistent with current dietary recommendations (36–38), the current study shows that saturated fat is the most harmful dietary constituent regarding IHTG accumulation. Because NAFLD increases the risk of type 2 diabetes, avoidance of foods rich in saturated fats might also help in prevention of diabetes.