| 1. |
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| 2. |
- Aminoff, A, et al.
(author)
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Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease.
- 2010
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In: Journal of lipid research. - 0022-2275 .- 1539-7262. ; 51:1, s. 103-11
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Journal article (peer-reviewed)abstract
- Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.
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| 3. |
- Anstee, Quentin M., et al.
(author)
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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort
- 2020
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:3, s. 505-515
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.METHODS: The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.RESULTS: Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.
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| 4. |
- Bunck, Mathijs C, et al.
(author)
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Effects of Exenatide on Measures of {beta}-Cell Function After 3 Years in Metformin-Treated Patients With Type 2 Diabetes.
- 2011
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In: Diabetes care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 34:9, s. 2041-2047
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Journal article (peer-reviewed)abstract
- OBJECTIVE We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI). RESULTS At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (-7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and -0.99 ± 0.65, respectively; P = 0.028). CONCLUSIONS EXE and GLAR sustained HbA(1c) over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.
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| 5. |
- Bunck, M. C., et al.
(author)
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Exenatide affected circulating cardiovascular risk biomarkers independently of changes in body composition
- 2010
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In: Diabetes Care. - 0149-5992. ; 33:8, s. 1734-1737
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Journal article (peer-reviewed)abstract
- OBJECTIVE To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. RESEARCH DESIGN AND METHODS Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. RESULTS Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. CONCLUSIONS Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.
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| 6. |
- Bunck, Mathijs C, et al.
(author)
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One-year treatment with exenatide vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and oxidative stress.
- 2010
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 212:1, s. 223-9
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The objective of the present study was to investigate the effects of one-year treatment with exenatide or Insulin Glargine, followed by a 5-week off-drug period, on postprandial lipidaemia, glycaemia and measures of oxidative stress. METHODS: Sixty-nine metformin-treated patients with type 2 diabetes were randomised (using apermuted block randomisation scheme stratified by site and baseline HbA(1c) stratum (< or = 8.5% or >8.5%) of which 60 completed (exenatide n=30; Insulin Glargine n=30) the pre-treatment and on-drug meal test. Postprandial glucose, lipids and lipoproteins, and oxidative stress markers were studied at week -1, 51, and after a 5-week off-drug period following a breakfast and lunch mixed-meal containing 50 g fat, 75 g carbohydrates, and 35 g protein. RESULTS: 51-Week exenatide treatment resulted in a significant reduction of prandial glucose, triglycerides, apo-B48, calculated VLDL-C, FFA and MDA excursions whereas Insulin Glargine predominantly reduced fasting glucose, FFA and MDA. Changes in markers of oxidative stress were related to changes in postprandial glucose and triglyceride excursions, independent of treatment arm. All postprandial measures returned to pre-treatment values in both groups after 5-week cessation of study treatment. CONCLUSION: Exenatide showed beneficial effects on postprandial glycaemia and lipidaemia, and these effects were related to changes in the oxidative stress markers MDA and oxLDL during one year of treatment as compared to Insulin Glargine. Following cessation of both exenatide and Insulin Glargine measures returned to pre-treatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.
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| 7. |
- Grimaudo, Stefania, et al.
(author)
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NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease.
- 2021
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In: Liver international. - : Wiley. - 1478-3231 .- 1478-3223. ; 41:11, s. 2712-2719
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Journal article (peer-reviewed)abstract
- Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis.We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n=124).The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62-0.95; P=.01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47-0.83; P=.001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67-0.98; P=.04). The C allele was associated with higher total circulating cholesterol (P=.01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis.Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR-targeted therapy warrants further investigation.
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| 8. |
- Hiukka, Anne, et al.
(author)
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Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus.
- 2008
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 1558-3597 .- 0735-1097. ; 52:25, s. 2190-7
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The aim of this substudy was to ascertain whether long-term treatment with fenofibrate reduces surrogate measures of atherosclerosis, biomarkers of inflammation, and endothelial activation in patients with type 2 diabetes. BACKGROUND: Some fibrates may decrease cardiovascular events, improve endothelial function, and reduce levels of acute-phase proteins. In the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study, fenofibrate failed to decrease the primary end point of coronary events in patients with type 2 diabetes. METHODS: A total of 170 patients with type 2 diabetes of the FIELD Helsinki cohort were randomly assigned to micronized fenofibrate 200 mg/day or placebo in a double-blind design. Carotid intima-media thickness (IMT) and the augmentation index (a measure of large artery stiffness) were measured at baseline and at second- and fifth-year visits. Plasma levels of interleukin (IL)-6, C-reactive protein (CRP), serum amyloid A (SAA), secretory phospholipase A2 IIA (SPLA2), E-selectin, vascular cellular adhesion molecule (VCAM)-1, and intercellular adhesion molecule (CAM)-1 were determined by commercial enzyme-linked immunosorbent assay kits at the same visits. RESULTS: IMT and the augmentation index increased similarly in both treatment groups during the study. Plasma levels of CRP, IL-6, SPLA2, SAA, VCAM-1, ICAM-1, and E-selectin remained unchanged in both groups. CONCLUSIONS: Fenofibrate treatment was not associated with beneficial changes in IMT, augmentation index, or biomarkers of inflammation and endothelial function. (Fenofibrate Intervention and Event Lowering in Diabetes; NCT00132886).
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| 9. |
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| 10. |
- Hyysalo, Jenni, et al.
(author)
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Circulating triacylglycerol signatures in nonalcoholic fatty liver disease associated with the I148M variant in PNPLA3 and with obesity
- 2014
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:1, s. 312-322
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Journal article (peer-reviewed)abstract
- We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3(I148M) gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3(I148M) gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3(148MM/148MI) compared with the PNPLA3(148II) group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulin-resistant. Liver fat was similarly increased in obese and PNPLA3(148MM/148MI) groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3(I148M) versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.
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| 11. |
- Hyötyläinen, Tuulia, 1971-, et al.
(author)
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Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease
- 2016
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In: Nature Communications. - London, United Kingdom : Nature Publishing Group. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.
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| 12. |
- Hyötyläinen, Tuulia, 1971-, et al.
(author)
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Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance
- 2012
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In: Molecular Biosystems. - : Royal Society of Chemistry. - 1742-206X .- 1742-2051. ; 8:10, s. 2559-2565
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Journal article (peer-reviewed)abstract
- While the molecular lipid composition of lipoproteins has been investigated in detail, little is known about associations of small polar metabolites with specific lipoproteins. The aim of the present study was to investigate the profiles of polar metabolites in different lipoprotein fractions, i.e., very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and two sub-fractions of the high-density lipoprotein (HDL). The VLDL, IDL, LDL, HDL(2), and HDL(3) fractions were isolated from serum of sixteen individuals having a broad range of insulin sensitivity and characterized using comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOFMS). The lipoprotein fractions had clearly different metabolite profiles, which correlated with the particle size and surface charge. Lipoprotein-specific associations of individual metabolites with insulin resistance were identified, particularly in VLDL and IDL fractions, even in the absence of such associations in serum. The results indicate that the polar molecules are strongly attached to the surface of the lipoproteins. Furthermore, strong lipoprotein-specific associations of metabolites with insulin resistance, as compared to their serum profiles, indicate that lipoproteins may be a rich source of tissue-specific metabolic biomarkers.
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| 13. |
- Jørgenrud, Benedicte, et al.
(author)
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The influence of sample collection methodology and sample preprocessing on the blood metabolic profile.
- 2015
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In: Bioanalysis. - : Future Science Ltd.. - 1757-6180 .- 1757-6199. ; 7:8, s. 991-1006
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Journal article (peer-reviewed)abstract
- AIM: Blood serum and plasma have intrinsic differences in their composition and the preprocessing, such as clotting temperature in serum, and storage at room temperature may have further effect on metabolite concentrations.METHODS: The influence of sampling preprocessing on the metabolic profiles in serum and different types of plasma was investigated using liquid chromatography and comprehensive 2D gas chromatography coupled to a mass spectrometer.RESULTS: The profiles of polar metabolites were significantly dependent on the type of the sample, while lipid profiles were similar in serum and different types of plasma. Extended storage of plasma at room temperature resulted in degradation of lipids already after 1 day. Serum clotting at room temperature generally resulted in higher metabolite concentration compared with serum clotting on ice.
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| 14. |
- Kolak, Maria, et al.
(author)
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Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity
- 2007
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 1960-1968
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Journal article (peer-reviewed)abstract
- OBJECTIVE: We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.RESEARCH DESIGN AND METHODS: A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.RESULTS: Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.CONCLUSIONS: Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.
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| 15. |
- Kolak, Maria, et al.
(author)
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Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue
- 2012
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In: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 11
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue.METHODS: Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject.RESULTS: Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot.CONCLUSIONS: Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.
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| 16. |
- Kotronen, Anna, et al.
(author)
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Comparison of lipid and fatty acid composition of the liver, subcutaneous and intra-abdominal adipose tissue, and serum
- 2010
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In: Obesity. - : Wiley-Blackwell Publishing Inc.. - 1930-7381 .- 1930-739X. ; 18:5, s. 937-944
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Journal article (peer-reviewed)abstract
- Ceramides may mediate saturated fat-induced insulin resistance, but there are no data comparing ceramide concentrations between human tissues. We therefore performed lipidomic analysis of human subcutaneous (SCfat) and intra-abdominal (IAfat) adipose tissue, the liver, and serum in eight subjects. The liver contained (nmol/mg tissue) significantly more ceramides (1.5-3-fold), sphingomyelins (7-8-fold), phosphatidylethanolamines (10-11-fold), lysophosphatidylcholines (7-12-fold), less ether-linked phosphatidylcholines (2-2.5-fold) but similar amounts of diacylglycerols as compared to SCfat and IAfat. The amounts of ceramides and their synthetic precursors, such as palmitic (16:0) free fatty acids and sphingomyelins, differed considerably between the tissues. The liver contained proportionally more palmitic, stearic (18:0), and long polyunsaturated fatty acids than adipose tissues. Stearoyl-CoA desaturase 1 (SCD1) activity reflected by serum, estimated from the 16:1/16:0-ratio, was closely related to that in the liver (r = 0.86, P = 0.024) but not adipose tissues. This was also true for estimated elongase (18:1/16:1, r = 0.89, P = 0.01), and Delta5 (20:4/20:3, r = 0.89, P = 0.012) and Delta6 (18:3[n-6]/18:2, r = 1.0, P < 0.001) desaturase activities. We conclude that the human liver contains higher concentrations of ceramides and saturated free fatty acids than either SCfat or IAfat.
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| 17. |
- Kotronen, Anna, et al.
(author)
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Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver
- 2009
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 58:1, s. 203-208
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine whether 1) hepatic ceramide and diacylglycerol concentrations, 2) SCD1 activity, and 3) hepatic lipogenic index are increased in the human nonalcoholic fatty liver.RESEARCH DESIGN AND METHODS: We studied 16 subjects with (n = 8) and without (n = 8) histologically determined nonalcoholic fatty liver (NAFL(+) and NAFL(-)) matched for age, sex, and BMI. Hepatic concentrations of lipids and fatty acids were quantitated using ultra-performance liquid chromatography coupled to mass spectrometry and gas chromatography.RESULTS: The absolute (nmol/mg) hepatic concentrations of diacylglycerols but not ceramides were increased in the NAFL(+) group compared with the NAFL(-) group. The livers of the NAFL(+) group contained proportionally less long-chain polyunsaturated fatty acids as compared with the NAFL(-) group. Liver fat percent was positively related to hepatic stearoyl-CoA desaturase 1 (SCD1) activity index (r = 0.70, P = 0.003) and the hepatic lipogenic index (r = 0.54, P = 0.030). Hepatic SCD1 activity index was positively related to the concentrations of diacylglycerols (r = 0.71, P = 0.002) but not ceramides (r = 0.07, NS).CONCLUSIONS: We conclude that diacylglycerols but not ceramides are increased in NAFL. The human fatty liver is also characterized by depletion of long polyunsaturated fatty acids in the liver and increases in hepatic SCD1 and lipogenic activities.
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| 18. |
- Lahelma, Mari, et al.
(author)
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Assessment of lifestyle factors helps to identify liver fibrosis due to non-alcoholic fatty liver disease in obesity
- 2021
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 13:1
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Journal article (peer-reviewed)abstract
- Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 ± 0.6 kg/m2 ) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3, TM6SF2, MBOAT7 and HSD17B13) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA1c, triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84–0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73–0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis.
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| 19. |
- Lahelma, Mari, et al.
(author)
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The human liver lipidome is significantly related to the lipid composition and aggregation susceptibility of low-density lipoprotein (LDL) particles
- 2022
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In: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 363, s. 22-29
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: The susceptibility of low-density lipoprotein (LDL) to aggregation predicts atherosclerotic cardiovascular disease. However, causes of interindividual variation in LDL lipid composition and aggregation susceptibility remain unclear. We examined whether the lipid composition and aggregation susceptibility of LDL reflect the lipid composition of the human liver.METHODS: Liver biopsies and blood samples for isolation of LDL particles were obtained from 40 obese subjects (BMI 45.9 ± 6.1 kg/m2, age 43 ± 8 years). LDL was isolated using sequential ultracentrifugation and lipidomic analyses of liver and LDL samples were determined using ultra-high performance liquid chromatography-mass spectrometry. LDL aggregation susceptibility ex vivo was analyzed by inducing aggregation by human recombinant secretory sphingomyelinase and following aggregate formation.RESULTS: The composition (acyl carbon number and double bond count) of hepatic triglycerides, phosphatidylcholines, and sphingomyelins (SMs) was closely associated with that of LDL particles. Hepatic dihydroceramides and ceramides were positively correlated with concentrations of the corresponding SM species in LDL as well with LDL aggregation. These relationships remained statistically significant after adjustment for age, sex, and body mass index.CONCLUSIONS: Lipid composition of LDL reflects that of the human liver in obese patients. Changes in hepatic sphingolipid metabolism may contribute to interindividual variation of LDL lipid composition and susceptibility to aggregation.
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| 20. |
- Lallukka, Susanna, et al.
(author)
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Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans
- 2017
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In: Thrombosis and Haemostasis. - 0340-6245. ; 117:2, s. 286-294
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Journal article (peer-reviewed)abstract
- Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant (‘IR’) versus insulin-sensitive (‘IS’)] and PNPLA3 genotype (PNPLA3148MM/ MI vs PNPLA3148II). Liver fat content (1H-MRS) was similarly increased in ‘IR’ (13 ± 1%) and PNPLA3148MM/MI (12 ± 2%) as compared to ‘IS’ (6 ± 1%, p<0.05) and PNPLA3148II (8 ± 1%, p<0.05), respectively. FVIII, FIX, FXIII, fibrinogen and VWF:RCo activities were increased, and PT and APTT shortened in ‘IR’ versus ‘IS’, in contrast to these factors being similar between PNPLA3148MM/MI and PNPLA3148II groups. In subjects undergoing a liver biopsy and entirely lacking the I148M variant, insulin-resistant subjects had higher hepatic expression of F8, F9 and FGG than equally obese insulin-sensitive subjects. Expression of pro-inflammatory genes in adipose tissue correlated positively with PT (% of normal), circulating FVIII, FIX, FXI, VWR:RCo and fibrinogen, and expression of anti-inflammatory genes negatively with PT (%), FIX and fibrinogen. We conclude that obesity/insulin resistance rather than an increase in liver fat is associated with a procoagulant plasma profile. This reflects adipose tissue inflammation and increased hepatic production of coagulation factors and their susceptibility for activation.
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| 21. |
- Lallukka, Susanna, et al.
(author)
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Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) - An 11-Year Prospective Study
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Journal article (peer-reviewed)abstract
- Liver fat can be non-invasively measured by proton magnetic resonance spectroscopy (1H-MRS) and fibrosis estimated as stiffness using transient elastography (FibroScan). There are no longitudinal data on changes in liver fat in Europids or on predictors of liver stiffness using these methods. We determined liver fat (1H-MRS) and clinical characteristics including features of insulin resistance at baseline and after a median follow-up period of 11.3 (range 7.3-13.4) years in 97 Finnish subjects. Liver stiffness was measured at 11.3 years. Liver fat content decreased by 5% (p < 0.05) over time. Values at baseline and 11.3 years were closely interrelated (r = 0.81, p < 0.001). Baseline liver fat (OR 1.32; 95%CI: 1.15-1.50) and change in BMI (OR 1.67; 95%CI: 1.24-2.25) were independent predictors of liver fat at 11.3 years (AUROC 0.90; 95%CI: 0.83-0.96). Baseline liver fat (AUROC 0.84; 95%CI: 0.76-0.92) predicted liver fat at 11.3 years more accurately than routinely available parameters (AUROC 0.76; 95%CI: 0.65-0.86, p = 0.02). At 11.3 years, 29% of the subjects had increased liver stiffness. Baseline liver fat (OR 2.17; 95%CI: 1.05-4.46) was an independent predictor of increased liver stiffness. These data show that liver fat is more important than the associated metabolic abnormalities as the predictor of future liver fat and fibrosis.
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| 22. |
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| 23. |
- Luukkonen, Panu K., et al.
(author)
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Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease
- 2022
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In: Journal of Hepatology. - : Elsevier BV. - 0168-8278. ; 76:3, s. 526-535
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Journal article (peer-reviewed)abstract
- Background & Aims: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) (‘MetComp’) and part by common modifiers of genetic risk (‘GenComp’). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. Methods: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). Results: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the ‘MetComp’. In contrast, the ‘GenComp’ was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. Conclusions: These data show that the mechanisms underlying ‘Metabolic’ and ‘Genetic’ components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. Lay summary: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
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| 24. |
- Luukkonen, Panu K., et al.
(author)
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Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease
- 2016
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In: Journal of Hepatology. - Amsterdam, Netherlands : Elsevier. - 0168-8278 .- 1600-0641. ; 64:5, s. 1167-1175
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver.METHODS: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither.RESULTS: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups.CONCLUSIONS: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease.
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| 25. |
- Luukkonen, Panu K., et al.
(author)
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Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids
- 2019
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In: JCI Insight. - : American Society for Clinical Investigation (ASCI). - 2379-3708. ; 4:16
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Journal article (peer-reviewed)abstract
- The common patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant I148M predisposes to nonalcoholic liver disease but not its metabolic sequelae. We compared the handling of labeled polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFA) in vivo in humans and in cells harboring different PNPLA3 genotypes. In 148M homozygous individuals, triglycerides (TGs) in very low-density lipoproteins (VLDL) were depleted of PUFAs both under fasting and postprandial conditions compared with 148I homozygotes, and the PUFA/SFA ratio in VLDL-TGs was lower relative to the chylomicron precursor pool. In human PNPLA3-148M and PNPLA3-KO cells, PUFA but not SFA incorporation into TGs was increased at the expense of phosphatidylcholines, and under lipolytic conditions, PUFA-containing diacylglycerols (DAGs) accumulated compared with PNPLA3-148I cells. Polyunsaturated TGs were increased, while phosphatidylcholines (PCs) were decreased in the human liver in 148M homozygous individuals as compared with 148I homozygotes. We conclude that human PNPLA3-I148M is a loss-of-function allele that remodels liver TGs in a polyunsaturated direction by impairing hydrolysis/transacylation of PUFAs from DAGs to feed phosphatidylcholine synthesis.
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