Fatty Liver A Novel Component of the Metabolic Syndrome

Department of Medicine, Division of Diabetes, University of Helsinki, Finland, FIN-00029 HUCH, Helsinki, Finland.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 02/2008; 28(1):27-38. DOI: 10.1161/ATVBAHA.107.147538
Source: PubMed


Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy.

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    • "The metabolic syndrome (MetS) manifests as a clustering of risk factors including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance, and prothrombotic and proinflammatory states [1] [2]. Individuals with MetS have at least a fivefold increased risk of developing type 2 diabetes (T2D), a twofold increased risk of cardiovascular diseases [3], and increased susceptibility to several other disorders including fatty liver disease [4], sleep apnea [5], and some forms of cancer [6]. "
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    ABSTRACT: The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86×10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63×10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37×10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52×10(-8), Pmeta=7.82×10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.
    Molecular Genetics and Metabolism 10/2015; DOI:10.1016/j.ymgme.2015.10.008 · 2.63 Impact Factor
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    • "Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis with increased risk of hepatocellular carcinoma [5] [6] [7]. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidemia and is now regarded as the liver manifestation of the metabolic syndrome (MetS) [8] [9] [10], a highly atherogenic condition even at a very early age [11] [12] [13]. When compared to control subjects who do not have hepatic steatosis, patients with NAFLD have a higher prevalence of atherosclerosis, as shown by increased carotid wall intimal thickness, increased numbers of atherosclerotic plaques, and increased plasma markers of endothelial dysfunction, which are independent of obesity and other established risk factors [13] [14] [15] [16] [17] [18] [19]. "
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    ABSTRACT: In the last 20 years, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide, primarily as a result of the epidemic of obesity. NAFLD is strongly associated with insulin resistance, glucose intolerance, and dyslipidemia and is currently regarded as the liver manifestation of the metabolic syndrome, a highly atherogenic condition even at a very early age. Patients with NAFLD including pediatric subjects have a higher prevalence of subclinical atherosclerosis, as shown by impaired flow-mediated vasodilation, increased carotid artery intima-media thickness, and arterial stiffness, which are independent of obesity and other established risk factors. More recent work has identified NAFLD as a risk factor not only for premature coronary heart disease and cardiovascular events, but also for early subclinical abnormalities in myocardial structure and function. Thus, we conducted a systematic review and meta-analysis to test the hypothesis that NAFLD is associated with evidence of subclinical cardiac structural and functional abnormalities.
    08/2015; 2015(5):213737. DOI:10.1155/2015/213737
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    • "Thus, a strong bidirectional association between NAFLD and MetS has been proposed . Insulin resistance, the key feature of MetS, is considered to play a central role in the first stages of fatty liver infiltration [13] [14] [15]. However, whether insulin resistance and hyperinsulinemia are components of MetS promoting fatty liver or whether NAFLD itself induces chronic hyperinsulinemia by impaired insulin degradation is still under debate. "
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    ABSTRACT: Background & aims: Non-alcoholic fatty liver disease was traditionally interpreted as a condition which may progress to liver-related complications. However, the increased mortality is primarily a result of cardiovascular diseases. It has been suggested that fatty liver can be considered as the hepatic consequence of the metabolic syndrome. The aim was to describe the different clinical presentations of non-alcoholic fatty liver disease on the basis of the patatin-like phospholipase domain-containing protein3 (PNPLA3) rs738409 gene variant. Methods: Fatty liver was defined by ultrasonographic Hamaguchi's criteria in 211 consecutive subjects with non-alcoholic fatty liver disease. The rs738409 polymorphism was determined by TaqMan assays. Metabolic syndrome was defined according to ATPIII modified criteria. Results: Prevalence of PNPLA3-148II, PNPLA3-148IM, and PNPLA3-148MM genotypes was 45.0%, 40.7%, and 14.3% respectively. Prevalence of metabolic syndrome progressively increased with the severity of liver steatosis (from 52.5% to 65.2%, and 82.3% respectively, p<0.01). The PNPLA3-148MM group had significantly lower mean serum triglycerides (p<0.001), Framingham cardiovascular risk score (p<0.01) and lower prevalence of metabolic syndrome (p<0.05) and its components. Age and HOMA-IR were positive independent predictors of metabolic syndrome, while a negative independent association was found between metabolic syndrome and the homozygotes PNPLA3 I148M variant. Conclusions: We suggest a lower prevalence of MetS and reduced cardiovascular risk in NAFLD patients with PNPLA3MM genotype.
    European Journal of Internal Medicine 06/2014; 25(6). DOI:10.1016/j.ejim.2014.05.012 · 2.89 Impact Factor
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