Prediction of Non-Alcoholic Fatty Liver Disease and Liver Fat Using Metabolic and Genetic Factors

Kotronen, Anna; Peltonen, Markku; Hakkarainen, Antti; Sevastianova, Ksenia; Bergholm, Robert; Johansson, Lina; Lundbom, Nina; Rissanen, Aila; Ridderstråle, Martin; Groop, Leif; Orho‐Melander, Marju; Yki‐Järvinen, Hannele

doi:10.1053/j.gastro.2009.06.005

Cited by 666 publications

(638 citation statements)

References 57 publications

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“…Beside the presence of the metabolic syndrome and type 2 diabetes and fasting serum insulin, raised AST levels and AST/ALT ratio are often used as independent predictors of liver fat and NAFLD (Kotronen et al., 2009). In the present study, we found a positive correlation between plasma AST levels and liver TAG ( r = 0.33, p = 0.05), confirming that increasing AST levels are related to the development of liver steatosis.…”

Section: Discussionmentioning

confidence: 99%

Liver and plasma lipid changes induced by cyclic fatty acid monomers from heated vegetable oil in the rat

Mboma

Leblanc

Wan

et al. 2018

Food Science & Nutrition

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Cyclic fatty acid monomers (CFAM) generated through domestic or industrial heating of vegetable oils may alter liver enzymes and induce hepatomegaly and steatosis, but the underlying mechanisms are not clearly understood. This study aimed to assess the effects of CFAM on liver and plasma lipids and to determine whether these effects are modulated by dietary lipids. Thirty‐six (36) male Wistar rats were fed either of the four isoenergetic diets consisting of canola oil or soybean oil with/without 500 mg/100 g CFAM of total fat for 28 days. Rats fed CFAM had higher liver total lipids (p = 0.03) and triacylglycerols (TAG) (p = 0.02), but less hepatic phosphatidylcholine (p = 0.02) compared to those fed the non‐CFAM diets. CFAM did not alter liver phosphatidylethanolamine N‐methyltransferase (PEMT) activity and CTP: phosphocholine cytidylyltransferase (CT‐α) protein levels. Rats fed CFAM diets had higher levels of plasma total cholesterol (TC), VLDL + LDL cholesterol, higher ratio of TC to HDL cholesterol, and lower levels of HDL cholesterol compared with rats fed non‐CFAM diets (p < 0.05). Plasma alanine transaminase (ALT) was decreased with CFAM, but plasma insulin, glucose, and TAG did not vary among the four diet groups (p < 0.05). Rats fed canola oil and CFAM had higher plasma levels of aspartate transaminase (AST) and AST/ALT ratio compared with the other three diet groups. These results indicate that CFAM may provoke an accumulation of TAG in the liver related to a decrease in phosphatidylcholine (PC) levels, but the effect of CFAM on PC concentrations may not occur through impairment of the two main PC biosynthesis pathways.

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Section: Discussionmentioning

confidence: 99%

Liver and plasma lipid changes induced by cyclic fatty acid monomers from heated vegetable oil in the rat

Mboma

Leblanc

Wan

et al. 2018

Food Science & Nutrition

View full text Add to dashboard Cite

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“…Methods such as ranked assessment (classifying as better, worse, or unchanged), or a truly quantitative measurement of the area of fibrosis by micromorphometry could be useful especially in early phase trials. Importantly, biomarkers for each cardinal feature of steatohepatitis [56][57][58][59][60][61][62] need to be developed and validated for longitudinal changes on therapy.…”

Section: Lessons For the Design Of Future Clinical Trialsmentioning

confidence: 99%

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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“…The volunteers for this cross-sectional study were recruited from those who had been previously genotyped at rs738409 in the PNPLA3 gene in our laboratory [18]. Exclusion criteria included: (1) heterozygous for the variant allele (PNPLA3-148MI); (2) pre-existing liver disease other than NAFLD (i.e.…”

Section: Participants and Study Designmentioning

confidence: 99%

“…The intensity differences arising from the acquisition parameters and localisation techniques were normalised as previously described, and liver fat content was expressed as a mass fraction [18]. We and others have previously validated the 1 H-MRS measurement against the histologically determined hepatic fat content [19,20].…”

Section: Measurement Of Liver Fat Contentmentioning

confidence: 99%

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

et al. 2013

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Aims/hypothesis The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD'=PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD'). Methods Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ( 1 H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2± 0.7 kg/m 2 ; non-obese 26.0±0.4 kg/m 2 ) or PNPLA3 genotype. All groups were similar with respect to age and sex.The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1 ± 1.3 kg/m 2 ; PNPLA3-148II, 31.2 ± 0.8 kg/m 2 ), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR. Results Liver fat was similarly increased in obese NAFLD (9.5±1.3% vs 5.1±0.9%, obese vs non-obese, p=0.007) and PNPLA3 NAFLD (11.4± 1.7% vs 5.3± 0.8%, PNPLA3-148MM vs PNPLA3-148II, p<0.001). Fasting serum insulin was higher in the obese than the non-obese group (76±6 vs 47±6 pmol/l, p<0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60±8 vs 62±5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups. Conclusions/interpretation PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features. Keywords

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Prediction of Non-Alcoholic Fatty Liver Disease and Liver Fat Using Metabolic and Genetic Factors

Cited by 666 publications

References 57 publications

Liver and plasma lipid changes induced by cyclic fatty acid monomers from heated vegetable oil in the rat

Liver and plasma lipid changes induced by cyclic fatty acid monomers from heated vegetable oil in the rat

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

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