Pathogenesis of non-alcoholic fatty liver disease

Dowman, Joanna; Tomlinson, Jeremy W.; Newsome, Philip N.

doi:10.1093/qjmed/hcp158

Cited by 647 publications

(599 citation statements)

References 140 publications

(142 reference statements)

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“…18 The exact etiology of NAFLD is not yet known, but hyperinsulinemia, insulin resistance and systemic inflammation are thought to play a major role in its pathogenesis. 19 Insulin resistance plays a central role in the vicious circle, which promotes lipolysis of the peripheral adipose tissue and increases the influx of free fatty acids into the liver. This insulin resistance leads to hyperinsulinemia, which increases the synthesis of serum uric acid (SUA) and decreases its renal excretion.…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of serum uric acid and insulin resistance are associated with nonalcoholic fatty liver disease among prediabetic subjects

Hossain¹

2016

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Background: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of insulin resistance and serum uric acid (SUA) levels seemed to be elevated during this disorder. There is a paucity of data regarding the association of SUA with NAFLD in prediabetes. In this context, the present study has been undertaken to investigate this association. Methods: In a cross-sectional analytical design, a total of 110 prediabetic subjects [M/F; 63/47, age in ranges, 45 (25-68)] were recruited in the study and divided into non NAFLD (n = 62) and NAFLD (n = 48) group after examined with ultrasonogram. Insulin resistance (HOMA-IR) was calculated by homeostasis model assessment. Results: NAFLD subjects had significantly higher levels of SUA compared to non NAFLD subjects (6.10 ± 1.42 vs. 5.38 ± 1.14, p = 0.004). They also had significantly higher levels of HOMA-IR (2.4 ± 1.09 vs. 1.4 ± 0.45, p < 0.001). In binary logistic regression analysis, HbA1c (OR = 3.505, p = 0.002), SUA (OR = 1.514, p = 0.023) and HOMA-IR (OR = 1.478, p = 0.029) were found to be significant determinants of NAFLD after adjusting the effects of BMI and triglyceride (TG). In multiple linear regression analysis, SUA showed significant positive association with HOMA-IR (ß = 0.355, p = 0.027) and TG (ß = 0.325, p = 0.033) after adjusting the effects of BMI and HbA1c. Conclusions: Increased levels of serum uric acid are significantly associated with NAFLD and this association seemed to be mediated by insulin resistance among prediabetic subjects.

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Section: Discussionmentioning

confidence: 99%

Elevated levels of serum uric acid and insulin resistance are associated with nonalcoholic fatty liver disease among prediabetic subjects

Hossain¹

2016

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“…The pathogenesis of NAFLD is not clearly defined, but there is a strong evidence in the literature that insulin resistance and visceral adiposity play major roles [18][19][20] . In our study, the prevalence of metabolic syndrome in patients with NAFLD was 26.4%, which is higher than that in the US general population (23.7%) [21] but is surprisingly lower than that reported in Iranian general population which was reported to be as high as 30%-31% [22,23] .…”

Section: Discussionmentioning

confidence: 99%

Elevated alanine aminotransferase activity is not associated with dyslipidemias, but related to insulin resistance and higher disease grades in non-diabetic non-alcoholic fatty liver disease

Ghamar-Chehreh

Amini

Khedmat

et al. 2012

Asian Pacific Journal of Tropical Biomedicine

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“…[1][2][3] The spectrum ranges from reversible fat accumulation (steatosis), which may be complicated by inflammation in steatohepatitis, to liver fibrosis, cirrhosis and ultimately organ loss. Although the exact mechanisms that determine the course of the disease remain elusive, hyperinsulinaemia and peripheral insulin resistance resulting in elevated levels of circulating free fatty acids appear to be among the principal causes of the initial steatosis.…”

Section: Introductionmentioning

confidence: 99%

“…Although the exact mechanisms that determine the course of the disease remain elusive, hyperinsulinaemia and peripheral insulin resistance resulting in elevated levels of circulating free fatty acids appear to be among the principal causes of the initial steatosis. 1 Steatosis and inflammation seem to influence each other mutually: steatosis rendering the liver more susceptible to proinflammatory cytokines and cytokines in turn impairing the regulation of lipid metabolism in hepatocytes. In addition to cytokines, small molecular mass mediators, including prostaglandins 4 are released from non-parenchymal liver cells and infiltrating inflammatory cells.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

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Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

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Pathogenesis of non-alcoholic fatty liver disease

Cited by 647 publications

References 140 publications

Elevated levels of serum uric acid and insulin resistance are associated with nonalcoholic fatty liver disease among prediabetic subjects

Elevated levels of serum uric acid and insulin resistance are associated with nonalcoholic fatty liver disease among prediabetic subjects

Elevated alanine aminotransferase activity is not associated with dyslipidemias, but related to insulin resistance and higher disease grades in non-diabetic non-alcoholic fatty liver disease

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

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