Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression

Heckmann, Bradlee L.; Zhang, Xiaodong; Saarinen, Alicia M.; Schoiswohl, Gabriele; Kershaw, Erin E.; Zechner, Rudolf; Li, Jun

doi:10.1172/jci.insight.88735

Cited by 30 publications

(31 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent evidence obtained from studies of adipose-specific ATGL and CGI-58 knockout mice has demonstrated that during fasting FAs derived from adipose lipolysis are critical for promoting hepatic G0S2 expression [80, 81]. Our co-culture experiments further revealed that the effect is the consequence of a direct induction of G0S2 gene transcription in hepatocytes by unsaturated FAs such as oleic acid and linoleic acid, which are released from lipolytically stimulated adipose tissue [81].…”

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 53%

“…Our co-culture experiments further revealed that the effect is the consequence of a direct induction of G0S2 gene transcription in hepatocytes by unsaturated FAs such as oleic acid and linoleic acid, which are released from lipolytically stimulated adipose tissue [81]. In the same study, we obtained compelling evidence that G0S2 is a direct target gene of liver X receptor α subtype (LXRα).…”

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 66%

“…These side effects render LXR agonists essentially useless in the clinical treatment of high cholesterol. The recent finding that G0S2 promotes TG deposition in response to LXR agonism has led to new insight into our understanding of the mechanism that underlies these TG-associated side effects of LXR agonists [81]. In particular, our data show that when G0S2 is ablated, T0901317 is rendered incapable of inducing plasma TG elevation and of causing hepatic steatosis while still retaining its positive effect on cholesterol/reverse cholesterol trafficking [81].…”

Section: Perspectives and Discussionmentioning

confidence: 82%

“…The PPARα agonist Wy14643 also failed to considerably increase G0S2 expression in liver in the absence of adipose FA influx [80]. Additionally, our most recent study showed that chemical antagonism of PPARα in mice elicited no effect on fasting-induced hepatic G0S2 expression [81]. Collectively, the existing evidence points to a more complex scenario of G0S2 regulation by PPARα.…”

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 99%

“…LXRα has previously been implicated in regulating hepatic TG accumulation both during fasting [85] and upon stimulation of de novo FA synthesis [86–89]. Using ChIP analysis and cell reporter assays, we demonstrated that transcriptional activation of G0S2 expression is conferred by LXRα binding to a direct repeat 4 (DR4) motif in the G0S2 promoter [81]. The importance of LXRα for G0S2 expression was further recognized in experiments using LXRα knockout mice where induction of both hepatic G0S2 expression by fasting or LXR agonist agonists was abolished [81].…”

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 99%

See 4 more Smart Citations

G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux

Zhang

Heckmann

Campbell

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

Self Cite

View full text Add to dashboard Cite

The discovery of adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) provided a major paradigm shift in the understanding of intracellular lipolysis in both adipocytes and nonadipocyte cells. The subsequent discovery of G0/G1 switch gene 2 (G0S2) as a potent endogenous inhibitor of ATGL revealed a unique mechanism governing lipolysis and fatty acid (FA) availability. G0S2 is highly conserved in vertebrates, and exhibits cyclical expression pattern between adipose tissue and liver that is critical to lipid flux and energy homeostasis in these two tissues. Biochemical and cell biological studies have demonstrated that a direct interaction with ATGL mediates G0S2’s inhibitory effects on lipolysis and lipid droplet degradation. In this review we examine evidence obtained from recent in vitro and in vivo studies that lends support to the proof-of-principle concept that G0S2 functions as a master regulator of tissue-specific balance of TG storage vs. mobilization, partitioning of metabolic fuels between adipose and liver, and the whole-body adaptive energy response.

show abstract

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 53%

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 66%

Section: Perspectives and Discussionmentioning

confidence: 82%

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 99%

Section: Regulation Of G0s2 Mrna and Protein Expressionmentioning

confidence: 99%

See 3 more Smart Citations

G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux

Zhang

Heckmann

Campbell

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

Self Cite

View full text Add to dashboard Cite

show abstract

Liver X Receptor Alpha Activation Inhibits Autophagy and Lipophagy in Hepatocytes by Dysregulating Autophagy‐Related 4B Cysteine Peptidase and Rab‐8B, Reducing Mitochondrial Fuel Oxidation

et al. 2021

View full text Add to dashboard Cite

Background and Aims Fat accumulation results from increased fat absorption and/or defective fat metabolism. Currently, the lipid‐sensing nuclear receptor that controls fat utilization in hepatocytes is elusive. Liver X receptor alpha (LXRα) promotes accumulation of lipids through the induction of several lipogenic genes. However, its effect on lipid degradation is open for study. Here, we investigated the inhibitory role of LXRα in autophagy/lipophagy in hepatocytes and the underlying basis. Approach and Results In LXRα knockout mice fed a high‐fat diet, or cell models, LXRα activation suppressed the function of mitochondria by inhibiting autophagy/lipophagy and induced hepatic steatosis. Gene sets associated with “autophagy” were enriched in hepatic transcriptome data. Autophagy flux was markedly augmented in the LXRα knockout mouse liver and primary hepatocytes. Mechanistically, LXRα suppressed autophagy‐related 4B cysteine peptidase (ATG4B) and Rab‐8B, responsible for autophagosome and ‐lysosome formation, by inducing let‐7a and microRNA (miR)‐34a. Chromatin immunoprecipitation assay enabled us to find LXRα as a transcription factor of let‐7a and miR‐34a. Moreover, 3’ untranslated region luciferase assay substantiated the direct inhibitory effects of let‐7a and miR‐34a on ATG4B and Rab‐8B. Consistently, either LXRα activation or the let‐7a/miR‐34a transfection lowered mitochondrial oxygen consumption rate and mitochondrial transmembrane potential and increased fat levels. In obese animals or nonalcoholic fatty liver disease (NAFLD) patients, let‐7a and miR‐34a levels were elevated with simultaneous decreases in ATG4B and Rab‐8B levels. Conclusions LXRα inhibits autophagy in hepatocytes through down‐regulating ATG4B and Rab‐8B by transcriptionally activating microRNA let‐7a‐2 and microRNA 34a genes and suppresses mitochondrial biogenesis and fuel consumption. This highlights a function of LXRα that culminates in the progression of liver steatosis and steatohepatitis, and the identified targets may be applied for a therapeutic strategy in the treatment of NAFLD.

show abstract

NF‐κB Regulation of LRH‐1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition–Associated Cholestasis

et al. 2021

View full text Add to dashboard Cite

BaCKgRoUND aND aIMS: Chronically administered parenteral nutrition (PN) in patients with intestinal failure carries the risk for developing PN-associated cholestasis (PNAC). We have demonstrated that farnesoid X receptor (FXR) and liver X receptor (LXR), proinflammatory interleukin-1 beta (IL-1β), and infused phytosterols are important in murine PNAC pathogenesis. In this study we examined the role of nuclear receptor liver receptor homolog 1 (LRH-1) and phytosterols in PNAC.

show abstract

Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression

Cited by 30 publications

References 59 publications

G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux

G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux

Liver X Receptor Alpha Activation Inhibits Autophagy and Lipophagy in Hepatocytes by Dysregulating Autophagy‐Related 4B Cysteine Peptidase and Rab‐8B, Reducing Mitochondrial Fuel Oxidation

NF‐κB Regulation of LRH‐1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition–Associated Cholestasis

Contact Info

Product

Resources

About