Liver X receptor in cooperation with SREBP‐1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease

Higuchi, Nobito; Kato, Masaki; Shundo, Yuki; Tajiri, H.; Tanaka, Masanori; Yamashita, Naoki; Kohjima, Motoyuki; Kotoh, Kazuhiro; Nakamuta, Makoto; Takayanagi, Ryoichi; Enjoji, Munechika

doi:10.1111/j.1872-034x.2008.00382.x

Cited by 238 publications

(170 citation statements)

References 33 publications

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“…Recently studies have shown that the acyl-CoA synthetase activity plays a key role in altering AMPK activation (28). Thus, ACSL3 knockdown could potentially alter AMPK activation, which is known to regulate numerous transcription factors to control gene expression (29,30). However, neither total AMPK nor phosphorylation of AMPK at Thr-172 were changed by ACSL3 knockdown (Fig.…”

Section: Journal Of Biological Chemistry 30479mentioning

confidence: 82%

“…Increased rates of de novo lipogenesis in obesity (40), hyperlipidemia (41), fatty liver disease (29), and type 2 diabetes (41) subjects suggests that conversion of surplus carbohydrate to lipids modulates hepatic function and contributes to the development of steatosis, insulin resistance, and dyslipidemia. Fatty acids derived from de novo lipogenesis are preferentially incorporated into storage lipids such as TAG and secreted as very low density lipoprotein rather than mitochondrial oxidation (19,42).…”

Section: Discussionmentioning

confidence: 99%

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Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Mashek

2009

Journal of Biological Chemistry

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Section: Journal Of Biological Chemistry 30479mentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Mashek

2009

Journal of Biological Chemistry

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“…In addition, its oxidized derivative, oxysterol, is an agonist of liver X receptor (LXR), which transactivates lipogenic transcriptional factors, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP) (15). However, …”

Section: Effects Of Nutritional Factors On the Expression Of Dpp4 Inmentioning

confidence: 99%

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

et al. 2011

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Abstract. Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic β-cells. DPP4 is also involved in the regulation of T cellmediated inflammatory processes. These properties of DPP4 suggest that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD). Hepatic DPP4 mRNA expression levels were analyzed by real-time PCR using liver biopsy samples from 17 NAFLD patients and 10 healthy subjects. In NAFLD patients, we also examined correlations between DPP4 expression levels and metabolic factors, including homeostasis model assessment-insulin resistance (HOMA-IR), body mass index (BMI), and serum cholesterol and triglyceride levels. To examine the potential effects of nutritional factors, DPP4 expression levels were analyzed in HepG2 cells subjected to various culture conditions. Hepatic DPP4 mRNA expression was significantly greater in NAFLD patients than in control subjects. DPP4 expression levels were negatively correlated with HOMA-IR and positively correlated with serum cholesterol levels. In HepG2 cells, high glucose significantly enhanced DPP4 expression, whereas insulin, fatty acids and cholesterol did not. Increased hepatic expression of DPP4 in NAFLD may be associated with metabolic factors, including insulin resistance, and may adversely affect glucose metabolism in this liver disease. IntroductionNon-alcoholic fatty liver disease (NAFLD) is a clinicopathological disorder characterized by the accumulation of triglycerides in hepatocytes. The incidence of NAFLD has increased markedly in recent years, accompanying the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) (1). More than 10% of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which is characterized by inflammatory cell infiltration and ballooning of hepatocytes in the liver. Liver cirrhosis and hepatocellular carcinoma occur in several patients with NASH (2). Obesity and insulin resistance (IR) are believed to be involved in the pathogenesis of NAFLD (3). Increased hepatic uptake of fatty acids as a result of elevated triglyceride degradation in adipose tissue causes hepatic fat accumulation. Reactive oxygen species (ROS) produced during lipid oxidation may induce hepatocyte death and inflammatory reactions. IR also reduces glucose uptake in muscles and diminishes insulin-dependent suppression of gluconeogenesis, ultimately progressing to T2DM (4).Dipeptidyl peptidase-4 (DPP4) inhibitors were recently introduced for the treatment of T2DM (5). DPP4 degrades glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from pancreatic β-cells. DPP4 inhibitors enhance glucose-dependent insulin secretion by suppressing GLP-1 degradation. However, the physiological functions of DPP4 are not fully understood. In addition to its effect on GLP-1, multiple activities of DPP4 have been reported in various cellular processes. Of note, DPP4 seems to influence inflammation by regu...

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“…Moreover, enhanced hepatic lipid production is induced by IR. Hyperglycemia induces the transactivation of transcriptional factors, carbohydrate responsive element binding protein and Liver X receptor, which are known to activate de novo hepatic lipid synthesis (5,6). Furthermore, triglyceride hydrolysis in the liver is also modified by IR.…”

Section: Introductionmentioning

confidence: 99%

Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease

Higuchi

Kato

Tanaka

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome, which is known to be associated with insulin resistance (IR). NAFLD occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and excretion as very low-density lipoprotein (VLDL). To estimate the effects of IR on hepatic lipid excretion, mRNA expression levels of genes involved in VLDL assembly were analyzed in NAFLD liver. Twenty-two histologically proven NAFLD patients and 10 healthy control subjects were enrolled in this study. mRNA was extracted from liver biopsy samples and real-time PCR was performed to quantify the expression levels of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP) and liver fattyacid binding protein (L-FABP). Hepatic expression levels of the genes were compared between NAFLD patients and control subjects. In NAFLD patients, we also examined correlations between expression levels of the genes and metabolic factors, including IR, and the extent of obesity and hepatic lipid accumulation. Hepatic expression levels of apoB, MTP and L-FABP were significantly up-regulated in NAFLD patients compared to control subjects. The expression levels of MTP were correlated with those of apoB, but not with those of L-FABP. In the NAFLD liver, the expression levels of MTP were significantly reduced in patients with HOMA-IR >2.5. In addition, a significant reduction in MTP expression was observed in livers with advanced steatosis. Enhanced expression of genes involved in VLDL assembly may be promoted to release excess lipid from NAFLD livers. However, the progression of IR and hepatic steatosis may attenuate this compensatory process.

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Liver X receptor in cooperation with SREBP‐1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease

Abstract: These findings suggest that LXR acts as one of the main regulators of lipid metabolism by regulating SREBP-1c expression in NAFLD.

Cited by 238 publications

References 33 publications

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease

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