Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH

Caballero, Francisco; Fernández, Anna; Lacy, Antonio M.; Fernández-Checa, José C.; Caballería, Juan; Garcı́a-Ruiz, Carmen

doi:10.1016/j.jhep.2008.12.016

Cited by 313 publications

(259 citation statements)

References 40 publications

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“…To investigate potential mechanisms between serum desmosterol and NASH, we measured total cholesterol and desmosterol in liver tissue as well (available from 62 subjects not differing from the total study group in age, gender distribution, and BMI, Supporting Table 4). As expected, [20][21][22] liver cholesterol correlated with steatosis (r ¼ 0.353, P ¼ 0.005), inflammation (r ¼ 0.421, P ¼ 0.001), and NAFLD activity score (r ¼ 0.378, P ¼ 0.002). The correlation of liver desmosterol with steatosis and inflammation was also significant, but of smaller magnitude ( Table 2).…”

Section: Resultssupporting

confidence: 78%

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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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Section: Resultssupporting

confidence: 78%

“…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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“…Deterioration in lipid uptake, transport, excretion, synthesis and catabolic mechanisms serves as the basis for NAFLD development (10). It is important to note that cholesterol content is increased in human fatty liver tissues (11)(12)(13)(14)(15), suggesting that cholesterol metabolism is dysregulated in NAFLD. However, the reason for the cholesterol accumulation is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

Liao¹,

Chen²,

Lee³

et al. 2011

Mol Med

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Nonalcoholic fatty liver disease (NAFLD) is associated with the development of metabolic syndromes and hepatocellular carcinoma (HCC). Cholesterol accumulation is related to NAFLD, whereas its detailed mechanism is not fully understood. Previously, we reported that glycine N-methyltransferase (GNMT) knockout (Gnmt ings and coimmunoprecipitation assays elucidated that the C conserved region (81-105 amino acids) of NPC2 interacts with the carboxyl-terminal fragment (171-295 amino acids) of GNMT. Confocal microscopy demonstrated that when cells were treated with low-density lipoprotein, NPC2 was released from lysosomes and interacts with GNMT in the cytosol. Overexpression of GNMT doubled the half-lives of both NPC2 isoforms and reduced cholesterol accumulation in cells. Furthermore, GNMT was downregulated in the liver tissues from patients suffering with NAFLD as well as from mice fed a high-fat diet, high-cholesterol diet or methionine/choline-deficient diet. In conclusion, our study demonstrated that GNMT regulates the homeostasis of cholesterol metabolism, and hepatic cholesterol accumulation may result from downregulation of GNMT and instability of its interactive protein NPC2. Novel therapeutics for steatohepatitis and HCC may be developed by using this concept.

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“…The potential for cholesterol metabolism disorders in NAFLD disease progression is suggested by reports that hepatic cholesterol accumulation enhances the progression of NAFLD to NASH in mouse models . A similar result appears in humans where free cholesterol levels in the liver are elevated in patients with NASH relative to patients with NAFLD or without fatty liver disease (Puri et al 2007, Caballero et al 2009). HMGR and SREBP2 transcript levels in liver were elevated in patients with NAFLD and NASH, providing a rationale for the elevated hepatic free cholesterol levels (Caballero et al 2009).…”

Section: Stard1 In Fatty Liver Diseasementioning

confidence: 59%

“…A similar result appears in humans where free cholesterol levels in the liver are elevated in patients with NASH relative to patients with NAFLD or without fatty liver disease (Puri et al 2007, Caballero et al 2009). HMGR and SREBP2 transcript levels in liver were elevated in patients with NAFLD and NASH, providing a rationale for the elevated hepatic free cholesterol levels (Caballero et al 2009). In this cohort, STARD1 mRNA was also increased in the liver with levels being highest in NASH patients.…”

Section: Stard1 In Fatty Liver Diseasementioning

confidence: 59%

The mammalian START domain protein family in lipid transport in health and disease

Clark¹

2011

Journal of Endocrinology

135

109

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Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved w210 amino acid sequence that folds into an a/b helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

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Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH

Cited by 313 publications

References 40 publications

Desmosterol in Human Nonalcoholic Steatohepatitis

Desmosterol in Human Nonalcoholic Steatohepatitis

Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis

The mammalian START domain protein family in lipid transport in health and disease

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