Hepatic Fatty Acid Transporter Cd36 Is a Common Target of LXR, PXR, and PPARγ in Promoting Steatosis

Zhou, Jie; Febbraio, Maria; Wada, Taira; Zhai, Yonggong; Kuruba, Ramalinga; He, Jinhan; Lee, Jung Hoon; Khadem, Shaheen; Ren, Shuling; Li, Song; Silverstein, Roy L.; Xie, Wen

doi:10.1053/j.gastro.2007.11.037

Cited by 505 publications

(422 citation statements)

References 47 publications

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“…67 Fatty acids outside the cell could be hydrolyzed by LPL (Lipoprotein lipase) and then transported into cells by CD36 (CD 36 molcule (thrombospondin receptor). 65 SCD (Stearoyl-CoA desaturase (delta-9-desaturase)) and DGAT1 (Diacylglycerol acyltransferase 1) are related to triglyceride synthesis. 41 The experimental results supported our hypothesis that miR-148a and miR-17-5p regulate fat metabolism in GMECs.…”

Section: Discussionmentioning

confidence: 99%

“…Fatty acids outside the cell could be hydrolyzed by LPL (Lipoprotein lipase) and then transported into cells by CD36 (CD 36 molcule (thrombospondin receptor). 65 SCD (Stearoyl-CoA desaturase (delta-9-desaturase)) is relate to triglyceride synthesis. 41 The results showed that overexpression of miR-148a upregulated (P < 0.05) the mRNA expression of SCD and CD36 (Fig.…”

Section: Microrna/mrna Profiling and Regulatory Fat Metabolism Networkmentioning

confidence: 99%

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miR-148a and miR-17–5p synergistically regulate milk TAG synthesis via PPARGC1A and PPARA in goat mammary epithelial cells

et al. 2017

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MicroRNA (miRNA) are a class of '18-25' nt RNA molecules which regulate gene expression and play an important role in several biologic processes including fatty acid metabolism. Here we used S-Poly (T) and high-throughput sequencing to evaluate the expression of miRNA and mRNA during early-lactation and in the non-lactating ("dry") period in goat mammary gland tissue. Results indicated that miR-148a, miR-17-5p, PPARGC1A and PPARA are highly expressed in the goat mammary gland in early-lactation and nonlactating periods. Utilizing a Luciferase reporter assay and Western Blot, PPARA, an important regulator of fatty acid oxidation, and PGC1a (PPARGC1A), a major regulator of fat metabolism, were demonstrated to be targets of miR-148a and miR-17-5p in goat mammary epithelial cells (GMECs). It was also revealed that miR-148a expression can regulate PPARA, and miR-17-5p represses PPARGC1A in GMECs. Furthermore, the overexpression of miR-148a and miR-17-5p promoted triacylglycerol (TAG) synthesis while the knockdown of miR-148a and miR-17-5p impaired TAG synthesis in GMEC. These findings underscore the importance of miR-148a and miR-17-5p as key components in the regulation of TAG synthesis. In addition, miR-148a cooperates with miR-17-5p to regulate fatty acid metabolism by repressing PPARGC1A and PPARA in GMECs. Further studies on the functional role of miRNAs in lipid metabolism of ruminant mammary cells seem warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Microrna/mrna Profiling and Regulatory Fat Metabolism Networkmentioning

confidence: 99%

miR-148a and miR-17–5p synergistically regulate milk TAG synthesis via PPARGC1A and PPARA in goat mammary epithelial cells

et al. 2017

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“…However, the molecular details of steatogenesis are not well understood. Several studies have demonstrated that the adipogenesis-related gene, PPAR-g, and its target gene, CD36, are responsible for fatty acid uptake and hepatic steatosis, 35,36 and that CD36-facilitated fatty acid uptake is regulated by membrane lipid rafts and caveolae. 31,37 Recently, it was reported that abnormal upregulation of CD36 on the plasma membrane of hepatocytes contributes to hepatic fat accumulation, insulin resistance, and hyper-insulinemia in patients with NAFLD.…”

Section: Discussionmentioning

confidence: 99%

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

Yimin

Furumaki

Matsuoka

et al. 2012

Laboratory Investigation

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Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steatosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factor (TNF)-a mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-a and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-a and inflammatory cell accumulation is dependent on IL-6. HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In this model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxLDL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH.

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“…As PGC-1␣ was originally identified as a coactivator of PPAR␥, we examined the ability of L-PGC-1␣ to coactivate the CD36 promoter containing a bona fide PPAR␥ response element with activity in liver (44). L-PGC-1␣ and PGC-1␣ showed comparable coactivation potencies when equimolar amounts of expression plasmids were used (Fig.…”

Section: L-pgc-1␣ and Pgc-1␣ Have Overlapping Coactivationmentioning

confidence: 99%

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

Felder

Soyal

Oberkofler

et al. 2011

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) is a transcriptional coactivator that contributes to the regulation of numerous transcriptional programs including the hepatic response to fasting. Mechanisms at transcriptional and post-transcriptional levels allow PGC-1␣ to support distinct biological pathways. Here we describe a novel human liver-specific PGC-1␣ transcript that results from alternative promoter usage and is induced by FOXO1 as well as glucocorticoids and cAMP-response element-binding protein signaling but is not present in other mammals. Hepatic tissue levels of novel and wild-type transcripts were similar but were only moderately associated (p < 0.003). Novel mRNA levels were associated with a polymorphism located in its promoter region, whereas wildtype transcript levels were not. Furthermore, hepatic PCK1 mRNA levels exhibited stronger associations with the novel than with the wild-type transcript levels. Except for a deletion of 127 amino acids at the N terminus, the protein, termed L-PGC-1␣, is identical to PGC-1␣. L-PGC-1␣ was localized in the nucleus and showed coactivation properties that overlap with those of PGC-1␣. Collectively, our data support a role of L-PGC-1␣ in gluconeogenesis, but functional differences predicted from the altered structure suggest that L-PGC-1␣ may have arisen to adapt PGC-1␣ to more complex metabolic pathways in humans. PGC-1␣2 (PPARGC1A) influences transcription in an exceptional variety of biological pathways including adaptive thermogenesis (1), mitochondrial biogenesis (2), skeletal muscle fiber determination and neuromuscular junction formation (3, 4), angiogenesis (5, 6), hepatic gluconeogenesis (7-9), fatty acid ␤-oxidation (10), regulation of clock genes (11), and protection of neural cells from reactive oxygen species (12, 13). Recent reviews describe the numerous functions of this fascinating protein (14 -17).Several levels of regulation have been implicated to explain the diverse roles of PGC-1␣ and its interactions with distinct transcription factors. For some pathways, expression levels of PGC-1␣ and transcription factors coactivated by PGC-1␣ are crucial (18). In addition, various signaling pathways target PGC-1␣ at the post-translational level. Such modifications detailed recently (19) alter the stability of PGC-1␣ and/or direct interactions with specific factors, thereby enhancing distinct transcriptional programs.Alternative splicing and/or transcription initiation, resulting in gain or deletion of interacting domains or signaling targets, represents another mode of regulation (15). Several PGC-1␣ isoforms have been reported in animal models (20,21). A short PGC-1␣ isoform was shown to be coexpressed with wild-type PGC-1␣ in mouse tissues and in human heart (22). The alternatively spliced mRNA is translated into a truncated protein, termed NT-PGC-1␣, that retains the N-terminal transactivation and nuclear receptor interaction domains and is functionally active.Knowledge about PGC-1␣ expression and regulation in human tissu...

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Hepatic Fatty Acid Transporter Cd36 Is a Common Target of LXR, PXR, and PPARγ in Promoting Steatosis

Cited by 505 publications

References 47 publications

miR-148a and miR-17–5p synergistically regulate milk TAG synthesis via PPARGC1A and PPARA in goat mammary epithelial cells

miR-148a and miR-17–5p synergistically regulate milk TAG synthesis via PPARGC1A and PPARA in goat mammary epithelial cells

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

Characterization of Novel Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Isoform in Human Liver

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