Increased Hepatic Synthesis and Dysregulation of Cholesterol Metabolism Is Associated with the Severity of Nonalcoholic Fatty Liver Disease

Min, Hae‐Ki; Kapoor, Ashwani; Fuchs, Michael; Mirshahi, Faridoddin; Zhou, Huiping; Maher, James W.; Kellum, John M.; Warnick, Ronald E.; Contos, Melissa J.; Sanyal, Arun J.

doi:10.1016/j.cmet.2012.04.004

Cited by 552 publications

(504 citation statements)

References 39 publications

(50 reference statements)

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“…16 In NAFLD, liver steatosis is associated with increased cholesterol synthesis and decreased cholesterol absorption. 17 Interestingly, triglyceride accumulation alone may not induce liver injury or inflammation, 18,19 whereas the accumulation of free cholesterol [20][21][22] and the dysregulation of the cholesterol synthesis pathway 23 relates to NASH.…”

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confidence: 99%

Desmosterol in Human Nonalcoholic Steatohepatitis

et al. 2013

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Dysregulation of the cholesterol synthesis pathway and accumulation of cholesterol in the liver are linked to the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we investigated the association of serum and liver levels of cholesterol precursors with NASH. Liver histology was assessed in 110 obese patients (Kuopio Obesity Surgery Study [KOBS] study, age 43.7 6 8.1 years [mean 6 standard deviation, SD], body mass index [BMI] 45.0 6 6.1 kg/m 2 ). Serum and liver levels of cholesterol precursors were measured with gas-liquid chromatography. The association between cholesterol precursors and serum alanine aminotransferase (ALT), as a marker of liver disease, was also investigated in a population cohort of 717 men (Metabolic Syndrome in Men Study [METSIM] study, age 57.6 6 5.8 years, BMI 27.1 6 4.0 kg/m 2 ). Serum desmosterol levels and the desmosterol-tocholesterol ratio were higher in individuals with NASH, but not in individuals with simple steatosis, compared to obese subjects with normal liver histology (P 5 0.002 and P 5 0.003, respectively). Levels of serum and liver desmosterol correlated strongly (r 5 0.667, P 5 1 3 10 29 ), suggesting a shared regulation. Both serum and liver desmosterol levels correlated positively with steatosis and inflammation in the liver (P < 0.05). Serum desmosterol had a higher correlation with the accumulation of cholesterol in the liver than serum cholesterol. Serum desmosterol levels (P 5 2 3 10 26 ) and the serum desmosterol-tocholesterol ratio (P 5 5 3 10 25 ) were associated with serum ALT in the population study. Conclusion: Levels of desmosterol in serum and the liver were associated with NASH. These results suggest that serum desmosterol is a marker of disturbed cholesterol metabolism in the liver. Whether desmosterol has a more specific role in the pathophysiology of NASH compared to other cholesterol precursors needs to be investigated. (HEPATOLOGY 2013;58:976-982)

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Desmosterol in Human Nonalcoholic Steatohepatitis

et al. 2013

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“…The roles of both triglycerides and free fatty acid accumulation in NAFLD have been elucidated in many studies 5 . By contrast, the role of cholesterol in NAFLD has been less extensively studied but is gaining increasing attention 1,[6][7][8] .…”

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“…Recent studies have demonstrated that cholesterol metabolism and trafficking might play an important role in the pathogenesis of NAFLD and NASH 1 . Cholesterol is highly enriched in LDLs and is taken up by the liver via receptor-mediated endocytosis of the LDL-LDL receptor complex at the plasma membrane.…”

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confidence: 99%

“…In the liver, receptor-mediated uptake of low-density lipoproteins (LDLs) and subsequent intracellular transport is essential for hepatic cholesterol homoeostasis and plasma lipoprotein metabolism. Dysfunction within this pathway results in liver disease such as non-alcoholic fatty liver disease (NAFLD), which is associated with increased cardiovascular and liver-related mortality 1 . NAFLD is the most common cause of chronic liver disease in Western Europe and the United States 2,3 .…”

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High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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“…14,36 Notably, miR-34a has been shown to be up-regulated in both human serum 50,51 and liver in humans and animal models of NAFLD. 14,55,121,122 Two recent studies suggest two differing mechanisms for the involvement of miR-34a in NASH pathogenesis through down-regulation of SIRT-1; a) leading to AMP kinase dephosphorylation and subsequent decreased phosphorylation of HMGCoA, ultimately leading to cholesterol accumulation 121 ; b) increased acetylation of p53 causing activation of apoptosis. 123 MiR-122 is significantly down-regulated in humans and animal models of NAFLD patients.…”

Section: Non-alcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

MicroRNAs in Liver Disease: Bench to Bedside

Shah

Nelson

Kowdley

2013

Journal of Clinical and Experimental Hepatology

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MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3 0 UTRs of mRNAs to promote degradation and/or block translation. Aberrant miR expression is associated with development of multiple diseases including hepatic diseases. The role of miRs in the regulation of gene expression and rapid progress in the field of microRNA research are resulting in momentum toward development of diagnostic markers and novel therapeutic strategies for human liver diseases. Recent studies provide clear evidence that miRs are abundant in the liver and modulate a diverse spectrum of biological functions, thereby supporting an association between alterations of miR homeostasis and pathological liver diseases. Here we review the role of miRs in liver as their physiological and pathological importance has been demonstrated in metabolism, immunity, viral hepatitis, oncogenesis, fatty liver diseases (alcoholic and non-alcoholic), drug-induced liver injury, fibrosis as well as acute liver failure. ( J CLIN EXP HEPATOL 2013;3:231-242)

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Increased Hepatic Synthesis and Dysregulation of Cholesterol Metabolism Is Associated with the Severity of Nonalcoholic Fatty Liver Disease

Cited by 552 publications

References 39 publications

Desmosterol in Human Nonalcoholic Steatohepatitis

Desmosterol in Human Nonalcoholic Steatohepatitis

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

MicroRNAs in Liver Disease: Bench to Bedside

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