Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes

Ren, Shuling; Li, Xiaobo; Rodríguez‐Agudo, Daniel; Gil, Gregorio; Hylemon, Phillip B.; Pandak, William M.

doi:10.1016/j.bbrc.2007.06.143

Cited by 55 publications

(61 citation statements)

References 40 publications

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“…6,48) The overexpression of FAS has promoted fatty acid synthesis and lipogenesis. [48][49][50] A previous study has also clarified that feeding ethanol in micropigs increased the expression of such lipogenic enzymes as SREBP-1c, FAS, acetyl-CoA carboxylase and stearoyl-CoA desaturase.…”

Section: Discussionmentioning

confidence: 97%

Depression by a Green Tea Extract of Alcohol-Induced Oxidative Stress and Lipogenesis in Rat Liver

Chen¹,

Li²,

Lin³

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionmentioning

confidence: 97%

Depression by a Green Tea Extract of Alcohol-Induced Oxidative Stress and Lipogenesis in Rat Liver

Chen¹,

Li²,

Lin³

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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“…Hepatic StAR expression was increased 7-and 15-fold in steatosis and NASH patients, respectively 11 , thereby enhancing mitochondrial free cholesterol accumulation and toxicity Heterozygous NPC1/2 deficiency leads to fatty liver, obesity and metabolic syndrome 82 NPC1 gene is linked to to early-onset and morbid adult obesity in Europeans 83 ORP8 ↓ hepatic cholesterol and triglyceride accumulation by inhibiting activation of SREBP-2 and SREBP-1c ORP8 ↑ hepatic insulin sensitivity through an AKTmediated mechanism 86,87 Cholesterol absorption and secretion [39][40][41] 25OHC3S had opposite effects than 25OHC on lipid metabolism and inflammation and improved NAFLD in cellular and mouse models( [39][40][41] Enhancement of on of SULT2B1b activity may counteract effects of toxic oxysterols …”

Section: Biological Effectmentioning

confidence: 99%

Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis

Musso

Gambino

Cassader

2013

Progress in Lipid Research

359

272

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IntroductionNonalcoholic fatty liver disease (NAFLD) affects 30% of the general adult population and 70-80% of diabetic and obese patients 1 . NAFLD encompasses a histological spectrum, ranging from simple steatosis (SS) to steatosis plus necroinflammation (nonalcoholic steatohepatitis, NASH).While SS is considered to have a benign hepatological prognosis, NASH confers a 1.8-fold higher mortality, largely accounted for by liver-related complications, and is a leading cause of liver transplantation 2, 3 . Furthermore, both histological subtypes confer an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD) 3 .The pathogenesis of NASH is unclear: the original "two-hit" hypothesis theorized that a first "hit" , namely hepatic steatosis, determined by metabolic factors (obesity, T2DM, dyslipidemia), sensitized the liver to subsequent "second hits", namely oxidative stress and proinflammatory cytokines, that cause hepatocellular injury and liver inflammation. The validity of this view has been recently challenged, and growing evidence suggests SS and NASH may actually be 2 separate diseases: in this "multi-parallel hit" model 4 , the accumulation of "lipotoxic/pro-inflammatory" lipid species interacts with proinflammatory factors to yield NASH since the beginning, while in the other cases the liver develops steatosis and remains free from inflammatory and fibrotic changes 5 . The type of toxic lipids has been the subject of extensive research: experimental inhibition of hepatic TG synthesis 6 and human hypobetalipoproteinemia, which does not progress to cirrhosis despite massive steatosis 7 , suggested that hepatic triglyceride (Tg) accumulation is not per se toxic, but rather protects the liver by buffering the accumulation of lipotoxic Tg precursors. Consistent with this view, subjects who are able to store excessive fat as neutral cholesterol esters and TG develop steatosis but not NASH and may be considered "good fat storers", while subjects who are unable to synthesize neutral lipids acccumulate toxic lipid species and develop progressive inflammation and fibrosis, leading to NASH. The search for the key toxic lipid species then focussed on free fatty acids (FFA), diacylglycerides, phospholipids (ceramides, sphingolipids), and most recently, free cholesterol (FC) 5 . Growing evidence connects altered cholesterol homeostasis 6 and hepatic FC accumulation to the pathogenesis of NASH. In the first National Health and Nutrition Examination Survey, higher dietary cholesterol consumption independently predicted a higher risk of cirrhosis 8 , and epidemiological data connect an increased cholesterol intake to the risk and severity of NAFLD 9, 10 . In NAFLD patients, the development of NASH and fibrosis paralleled hepatic FC accumulation 11, 12 . Experimental induction of hepatic FC accumulation promoted steatohepatitis and fibrosis 13, 14, 15 , while correction of hepatic FC overload improved liver disease severity in NASH 16, 17,18,19,20, 21,22, 23 . We will review cellular mechanisms of choles...

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“…This sulfated oxysterol was believed to be initially synthesized by CYP27A1 in mitochondria (15). It has been reported that the addition of 25HC3S to primary human hepatocytes decreases cholesterol and fatty acid biosynthesis by blocking the activation of sterol-regulatory element binding protein-1c and inhibiting its expression (16). These results suggest that 25HC3S plays an important role in the maintenance of intracellular cholesterol and lipid homeostasis.…”

mentioning

confidence: 99%

“…However, to date, little is known about the role of SULTs in cholesterol metabolism in the liver. It is likely that SULT2B1b is involved in oxysterol sulfation, which plays an important role in lipid metabolism in liver (16).…”

mentioning

confidence: 99%

Biosynthesis of the regulatory oxysterol, 5-cholesten-3β,25-diol 3-sulfate, in hepatocytes

Pandak

Erickson

et al. 2007

Journal of Lipid Research

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Cellular cholesterol homeostasis is maintained through coordinated regulation of cholesterol synthesis, degradation, and secretion. Nuclear receptors for oxygenated cholesterol derivatives (oxysterols) are known to play key roles in the regulation of cholesterol homeostasis. We recently identified a sulfated oxysterol, 5-cholesten-3b,25-diol 3-sulfate (25HC3S), that is localized to liver nuclei. The present study reports a biosynthetic pathway for 25HC3S in hepatocytes. Assays using mitochondria isolated from rats and sterol 27-hydroxylase (Cyp27A1) gene knockout mice indicated that 25-hydroxycholesterol (25HC) is synthesized by CYP27A1. Incubation of cholesterol or 25HC with mitochondrial and cytosolic fractions in the presence of 3 ¶-phosphoadenosyl 5 ¶-phosphosulfate resulted in the synthesis of 25HC3S. Real-time RT-PCR and Western blot analysis showed the presence of insulin-regulated hydroxycholesterol sulfotransferase 2B1b (SULT2B1b) in hepatocytes. 25HC3S, but not 25HC, decreased SULT2B1b mRNA and protein levels. Specific small interfering RNA decreased SULT2B1b mRNA, protein, and activity levels. These findings demonstrate that mitochondria synthesize 25HC, which is subsequently 3b-sulfated to form 25HC3S.-Li, X., W. M. Pandak, S. K. Erickson, Y. Ma, L. Yin, P. Hylemon, and S. Ren. Biosynthesis of the regulatory oxysterol, 5-cholesten-3b,25-diol 3-sulfate, in hepatocytes.

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Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes

Cited by 55 publications

References 40 publications

Depression by a Green Tea Extract of Alcohol-Induced Oxidative Stress and Lipogenesis in Rat Liver

Depression by a Green Tea Extract of Alcohol-Induced Oxidative Stress and Lipogenesis in Rat Liver

Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis

Biosynthesis of the regulatory oxysterol, 5-cholesten-3β,25-diol 3-sulfate, in hepatocytes

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