Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

Kanth, Vishnubhotla Venkata Ravi; Sasikala, Mitnala; Sharma, Mithun; Rao, Padaki Nagaraja; Reddy, D. Nageshwar

doi:10.4254/wjh.v8.i20.827

Cited by 20 publications

(16 citation statements)

References 64 publications

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“…Finally, genome‐wide association studies showed an association between the HSD17B13 locus and fatty liver disease (http://www.ncbi.nlm.nih.gov/pmc/?term=hsd17b13%20NAFLD). (40, 50–56) However, all these studies are based on HSD17B13 mRNA expression, which could not always reflect the protein expression or activity of the enzyme. Further studies are required to clarify how expression and activity of HSD17B13 are modulated with FLD.…”

Section: Discussionmentioning

confidence: 99%

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

Adam

Heikelä

Sobolewski³

et al. 2018

FASEB j.

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Hydroxysteroid (17β) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd17b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcarnitines, suggesting impaired mitochondrial β-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsd17b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.-Adam, M., Heikelä, H., Sobolewski, C., Portius, D., Mäki-Jouppila, J., Mehmood, A., Adhikari, P., Esposito, I., Elo, L. L., Zhang, F.-P., Ruohonen, S. T., Strauss, L., Foti, M., Poutanen, M. Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.

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Section: Discussionmentioning

confidence: 99%

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

Adam

Heikelä

Sobolewski³

et al. 2018

FASEB j.

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“…Whole exome sequencing studies performed on obese Caucasian participants with NAFLD have revealed deleterious mutations in Bardet-Biedl syndrome 1 gene as well as the Melanocortin 3 receptor gene[58]. In 2008, the first genome wide association study was published; it examined hepatic triacylglycerol (HTAG) accumulation and identified association with increased HTAG and the PNPLA3 gene[59].…”

Section: Geneticsmentioning

confidence: 99%

Non-alcoholic fatty liver disease: An expanded review

Benedict

Zhang

2017

WJH

624

494

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Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the “magic bullet” in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.

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“…Apart from environmental factors various studies have now confirmed the role of genetics in conferring susceptibility to the disease. Diseases with complex traits including NAFLD result from interactions between environment and polygenic genetic susceptibility made up of many independent modifiers[ 8 ]. Family aggregation, studies on twins and differences in susceptibility and progression suggest a significant heritable component to NAFLD that may be classified under “common disease-common variant” hypothesis[ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Carrier of the minor allele and 148M was associated with a twofold increase in HTGC (Hepatic triglyceride content)[ 10 ]. Subsequent to this, the SNP was replicated in almost all the ethnicities successfully[ 8 ]. Further, two exome wide association studies[ 11 , 12 ] carried out independently in African-American and Norwegian ethnicities identified that a variant rs58542926 (p.E167K) in TM6SF2 gene was associated with susceptibility to NAFLD, influencing total cholesterol levels and enhanced risk of myocardial infarction.…”

Section: Introductionmentioning

confidence: 99%

Regional differences in genetic susceptibility to non-alcoholic liver disease in two distinct Indian ethnicities

Govardhan¹,

Steffie²,

Kanth³

et al. 2017

WJH

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AIMTo validate the association of variants in PNPLA3 (rs2281135) and TM6SF2 (rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease (NAFLD).METHODSA total of 503 individuals with and without fatty infiltration were recruited. Fatty infiltration was confirmed based on ultrasound findings. Anthropometric data and blood samples were collected from the study group. DNA was isolated from peripheral blood, quality and quantity was assessed by gel electrophoresis and spectrophotometer respectively. Genotyping of the variants in PNPLA3 and TM6SF2 genes was carried out by employing taqman probes (C_15875080_10 for PNPLA3 and C_8946351_10 for TM6SF2 SNP) on real time PCR (Stepone-Lifetechnologies). Genotype data was tested for deviations from Hardy-Weinberg equilibrium. χ2 test was used to analyze the statistical significance of the difference in genotype distribution of the studied variants in patients and controls and the strength of association was expressed as odds ratio (95%CI). A two-tailed P value of ≤ 0.05 was considered statistically significant.RESULTSThe study group comprised of 503 individuals of which 256 had fatty infiltration and 247 without fatty infiltration and thus formed the patient and control groups respectively. As the patient group could be divided in to two distinct ethnicities (ancestral South Indians-ASI and North-East Indians-NEI), further recruitment of control cohort and association analyses was carried out based on ethnicities. Of the 256 with fatty infiltration 93 were ASI and 163 were NEI and of the 247 controls 138 were ASI and 109 were NEI. As expected, there were significant differences in the anthropometric and other clinical data between the control and the patient groups. However significant differences within the ethnicities were also noted. While rs2281135 in PNPLA3 gene was significantly associated (P = 0.03) with higher risk (odds 1.9, 95%CI: 1.5-3.14, P = 0.03) of NAFLD in NEI ethnicity, rs58542926 in TM6SF2 gene was significantly associated with NAFLD with a 2.7 fold higher risk (odds 2.7, 95%CI: 1.37-5.3, P = 0.0004) of the disease. There were significantly higher proportions of individuals with variants in both the genes in the patient group in both ASI (patients - 14/93 and controls - 7/138; P = 0.009) and NEI ethnicities (patients - 17/163 and controls - 7/109; P = 0.01).CONCLUSIONAlthough the study identified distinct genetic susceptibility in the two ethnicities, transheterozygosity of the variants suggests higher risk of NAFLD in individuals with both the variants.

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Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

Cited by 20 publications

References 64 publications

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

Non-alcoholic fatty liver disease: An expanded review

Regional differences in genetic susceptibility to non-alcoholic liver disease in two distinct Indian ethnicities

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