| 1. |
- de Mello, Vanessa D., et al.
(författare)
-
Serum aromatic and branched-chain amino acids associated with NASH demonstrate divergent associations with serum lipids
- 2021
-
Ingår i: Liver International. - : Wiley. - 1478-3223 .- 1478-3231. ; 41:4, s. 754-763
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has been associated with multiple metabolic abnormalities. By applying a non-targeted metabolomics approach, we aimed at investigating whether serum metabolite profile that associates with NAFLD would differ in its association with NAFLD-related metabolic risk factors. Methods & Results: A total of 233 subjects (mean ± SD: 48.3 ± 9.3 years old; BMI: 43.1 ± 5.4 kg/m2; 64 male) undergoing bariatric surgery were studied. Of these participants, 164 with liver histology could be classified as normal liver (n = 79), simple steatosis (SS, n = 40) or non-alcoholic steatohepatitis (NASH, n = 45). Among the identified fasting serum metabolites with higher levels in those with NASH when compared to those with normal phenotype were the aromatic amino acids (AAAs: tryptophan, tyrosine and phenylalanine), the branched-chain amino acids (BCAAs: leucine and isoleucine), a phosphatidylcholine (PC(16:0/16:1)) and uridine (all FDRp < 0.05). Only tryptophan was significantly higher in those with NASH compared to those with SS (FDRp < 0.05). Only the AAAs tryptophan and tyrosine correlated positively with serum total and LDL cholesterol (FDRp < 0.1), and accordingly, with liver LDLR at mRNA expression level. In addition, tryptophan was the single AA associated with liver DNA methylation of CpG sites known to be differentially methylated in those with NASH. Conclusions: We found that serum levels of the NASH-related AAAs and BCAAs demonstrate divergent associations with serum lipids. The specific correlation of tryptophan with LDL-c may result from the molecular events affecting LDLR mRNA expression and NASH-associated methylation of genes in the liver.
|
|
| 2. |
- Grimaudo, Stefania, et al.
(författare)
-
NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease.
- 2021
-
Ingår i: Liver international. - : Wiley. - 1478-3231 .- 1478-3223. ; 41:11, s. 2712-2719
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 3. |
- Järvelä-Reijonen, Elina, et al.
(författare)
-
Sleep-time physiological recovery is associated with eating habits in distressed working-age Finns with overweight : Secondary analysis of a randomised controlled trial
- 2021
-
Ingår i: Journal of Occupational Medicine and Toxicology. - : BioMed Central (BMC). - 1745-6673. ; 16:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Association of physiological recovery with nutrition has scarcely been studied. We investigated whether physiological recovery during sleep relates to eating habits, i.e., eating behaviour and diet quality. Methods: Cross-sectional baseline analysis of psychologically distressed adults with overweight (N = 252) participating in a lifestyle intervention study in three Finnish cities. Recovery measures were based on sleep-time heart rate variability (HRV) measured for 3 consecutive nights. Measures derived from HRV were 1) RMSSD (Root Mean Square of the Successive Differences) indicating the parasympathetic activation of the autonomic nervous system and 2) Stress Balance (SB) indicating the temporal ratio of recovery to stress. Eating behaviour was measured with questionnaires (Intuitive Eating Scale, Three-Factor Eating Questionnaire, Health and Taste Attitude Scales, ecSatter Inventory (TM)). Diet quality was quantified using questionnaires (Index of Diet Quality, Alcohol Use Disorders Identification Test Consumption) and 48-h dietary recall. Results: Participants with best RMSSD reported less intuitive eating (p = 0.019) and less eating for physical rather than emotional reasons (p = 0.010) compared to those with poorest RMSSD; participants with good SB reported less unconditional permission to eat (p = 0.008), higher fibre intake (p = 0.028), higher diet quality (p = 0.001), and lower alcohol consumption (p < 0.001) compared to those with poor SB, although effect sizes were small. In subgroup analyses among participants who reported working regular daytime hours (n = 216), only the associations of SB with diet quality and alcohol consumption remained significant. Conclusions: Better nocturnal recovery showed associations with better diet quality, lower alcohol consumption and possibly lower intuitive eating. In future lifestyle interventions and clinical practice, it is important to acknowledge sleep-time recovery as one possible factor linked with eating habits.
|
|
| 4. |
- Männistö, Ville, et al.
(författare)
-
Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition
- 2021
-
Ingår i: Hepatology Communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 5, s. 244-257
-
Tidskriftsartikel (refereegranskat)abstract
- The protein phosphatase 1 regulatory subunit 3B (PPP1R3B) gene is a target of farnesoid X receptor (FXR), which is a major regulator of bile acid metabolism. Both PPP1R3B and FXR have been suggested to take part in glycogen metabolism, which may explain the association of PPP1R3B gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of PPP1R3B rs4240624 variant on bile acid composition in individuals with obesity. The study cohort consisted of 242 individuals from the Kuopio Obesity Surgery Study (73 men, 169 women, age 47.6 ± 9.0 years, body mass index 43.2 ± 5.4 kg/m2) with PPP1R3B genotype and liver RNA sequencing (RNA-seq) data available. Fasting plasma and gallbladder bile samples were collected from 50 individuals. Bile acids in plasma did not differ based on the PPP1R3B rs4240624 genotype. However, the concentration of total bile acids (109 ± 55 vs. 35 ± 19 mM; P = 1.0 × 10−5) and all individual bile acids (also 7α-hydroxy-4-cholesten-3-one [C4]) measured from bile were significantly lower in those with the AG genotype compared to those with the AA genotype. In addition, total cholesterol (P = 0.011) and phospholipid (P = 0.001) levels were lower in individuals with the AG genotype, but cholesterol saturation index did not differ, indicating that the decrease in cholesterol and phospholipid levels was secondary to the change in bile acids. Liver RNA-seq data demonstrated that expression of PPP1R3B, tankyrase (TNKS), Homo sapiens chromosome 8 clone RP11-10A14.5 (AC022784.1 [LOC157273]), Homo sapiens chromosome 8 clone RP11-375N15.1 (AC021242.1), and Homo sapiens chromosome 8, clone RP11-10A14 (AC022784.6) associated with the PPP1R3B genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. Conclusion: The rs4240624 variant in PPP1R3B has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect.
|
|
| 5. |
- Oveis, Jamialahmadi, et al.
(författare)
-
Exome-wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated with Fatty Liver Disease.
- 2021
-
Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 160:5, s. 1634-1646.E7
-
Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered.To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase (ALT) at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8,930 participants in whom liver fat measurement was available, and replicated two genetic variants in three independent cohorts comprising 2,621 individuals with available liver biopsy.We identified 190 genetic variants independently associated with ALT after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver.We identified two novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
|
|
| 6. |
- Stefania, Grimaudo, et al.
(författare)
-
PCSK9 rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD.
- 2021
-
Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - : Wiley. - 1478-3231. ; 41:2, s. 321-332
-
Tidskriftsartikel (refereegranskat)abstract
- The proproteinconvertasesubtilisin/kexin type 9(PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower LDL-C levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models.We considered 1,874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9,was genotyped by TaqMan assays. We also evaluated 1)PCSK9 mRNA hepatic expression in human liver, and 2)the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9.Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against NAFLD (OR0.42; 95%C.I0.22-0.81; P=0.01), NASH (OR0.48;95%C.I.0.26-0.87;P=0.01)and more severe fibrosis (OR0.55; 95%C.I.0.32-0.94; P=0.03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis(P=0.03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge.In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting PCSK9 inhibition may be a new therapeutic strategy to treat NASH.
|
|
| 7. |
- Tanaka, Yuki, et al.
(författare)
-
LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.
- 2021
-
Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 70, s. 180-193
-
Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.We generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.The hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.
|
|
