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KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression
Open accessAbstract
Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic TG is a hallmark of nonalcoholic fatty liver disease, which is associated with obesity and insulin resistance. Here, we show that KH-type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of period 2 (Per2) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp(-/-) livers. Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis. Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP. Similar to Ksrp(-/-) livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp(-/-) hepatocytes due to increased Per2 expression. Using heterologous mRNA reporters, we show that the AU-rich element-containing 3' untranslated region of Per2 is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability.
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Written from the paper’s full text.
TL;DR
KSRP ablation lowers hepatic triglyceride content and protects mice from diet-induced hepatosteatosis by increasing Per2 mRNA stability and altering circadian clock/lipogenic gene expression in liver. KSRP directly binds the AU-rich element AU2 in the Per2 3′ UTR to promote Per2 mRNA decay, and increased PER2 represses Srebp1c/Pparg and de novo lipogenesis.
Key findings
- Ksrp−/− mice had reduced hepatic TG under chow and high-fat diet (HFD); on HFD, hepatic TG was reduced by 30–50% under fed and fasting conditions, with lower fed serum TG and no difference in hepatic cholesterol.
- Ksrp−/− livers showed elevated Per2 mRNA in the dark period and a delayed phase (≈4 h) in oscillations of Per1, Clock, Rev-erba, Bmal1, and Dbp; PER2 protein was also increased, while CLOCK and BMAL1 were not altered.
- KSRP promoted Per2 mRNA decay via direct RNA-protein interaction: Per2 mRNA stability increased in Ksrp−/− hepatocytes, and the distal Per2 3′ UTR reporter hGB-Per2 669 had a half-life of 3.6 h in wild-type MEFs, with impaired decay in Ksrp−/− MEFs; AU2 mutation impaired decay and KSRP bound AU2 with high affinity.
- In Ksrp−/− hepatocytes, lipogenic genes (Acaca, Fasn, Scd1) and intracellular TG were reduced; Per2 knockdown restored lipogenic gene expression and TG levels, while PER2 overexpression downregulated Srebp1c, Pparg, Acaca, Fasn, and Scd1 and reduced TG.
Methods
- Male Ksrp-null C57BL/6J mice and wild-type controls, 10–16 weeks old, maintained on 12 h light/12 h dark and fed normal chow or HFD (45% kcal from fat) for 6–8 weeks; tissues collected at 4 h intervals across the light-dark cycle.
- Primary hepatocytes and mouse embryonic fibroblasts were used with siRNA knockdown, plasmid overexpression, dexamethasone synchronization, actinomycin D mRNA decay assays, qPCR, immunoblotting, immunoprecipitation, ribonucleoprotein immunoprecipitation, RNA binding/UV cross-linking, and luciferase/globin reporter assays.
- Hepatic and serum lipids were measured enzymatically; data presented as mean ± SEM and analyzed by unpaired two-tailed Student’s t-test or one-way ANOVA.
Limitations
- Stated: the authors cannot rule out that reduced TG in Ksrp−/− livers is due to altered nutritional state rather than altered rhythmic clock/lipid gene expression, though diurnal food intake was not altered; the exact mechanism awaits further studies.
- Stated: they cannot exclude that reduced or altered fatty acid uptake also contributes to lower TG, since Cd36, Slc27a2, and Ldlr expression was decreased or phase-shifted; they also did not examine oscillation of remaining PER2 protein after Per2 knockdown.
- Evident: the model is global Ksrp-null, not liver-specific, so systemic effects cannot be excluded; the authors propose future liver-specific KSRP and Per2 knockout studies. They also note KSRP’s roles in apoB editing and pri-miRNA processing may complicate therapeutic targeting.
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- Findingown data
Circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp-/- livers.
“Expression of period 2 ( Per2 ) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp ؊ / ؊ livers.”
Quote in the paperSubstantial claim - Findingown data
Diurnal expression of some lipid metabolism genes is disturbed with reduced expression of genes involved in de novo lipogenesis in Ksrp-/- livers.
“Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis.”
Quote in the paperSubstantial claim - Findingown data
KSRP promotes decay of Per2 mRNA through an RNA-protein interaction.
“Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP.”
Quote in the paperSubstantial claim - Findingown data
Ksrp-/- mice exhibit typical entrainment to light cycles in LD.
“Ksrp Ϫ / Ϫ mice exhibited typical entrainment to the light cycles compared with wild-type mice in LD ( Fig. 3A ).”
Quote in the paperNot a substantial claim - Findingown data
Per2 mRNA levels are elevated at 24 h and thereafter after Dex treatment in Ksrp-/- hepatocytes.
“Per2 mRNA levels were elevated at 24 h and thereafter after Dex treatment in Ksrp Ϫ / Ϫ hepatocytes ( Fig. 5A ).”
Quote in the paperSubstantial claim
- Findingown data
When fed a high-fat diet, Ksrp-/- mice show a 30-50% reduction in hepatic TG levels under both fed and fasting conditions.
“When fed a HFD, Ksrp Ϫ / Ϫ mice showed a 30-50% reduction in hepatic TG levels under both fed and fasting conditions ( Fig. 1A ).”
Quote in the paperSubstantial claim - Findingown data
Expression of Per2 is increased during the dark period in Ksrp-/- livers.
“Expression of period 2 ( Per2 ) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp ؊ / ؊ livers.”
Quote in the paperSubstantial claim - Findingown data
Both expression of lipogenic genes and intracellular TG levels are reduced in Ksrp-/- hepatocytes due to increased Per2 expression.
“Similar to Ksrp ؊ / ؊ livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp ؊ / ؊ hepatocytes due to increased Per2 expression.”
Quote in the paperSubstantial claim - Findingown data
In DD, Ksrp-/- mice show a moderately lengthened free-running period (WT 23.7 h vs Ksrp-/- 23.9 h).
“In DD, Ksrp Ϫ / Ϫ mice showed a moderately lengthened free-running period (wild-type = 23.7 h vs. Ksrp Ϫ / Ϫ = 23.9h; Fig. 3A, B ).”
Quote in the paperNot a substantial claim - Findingown data
KSRP ablation reduces hepatic TG levels.
“Here, we show that KH-type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis.”
Quote in the paperSubstantial claim - Findingown data
The AU-rich element-containing 3' UTR of Per2 is responsible for KSRP-dependent mRNA decay.
“Using heterologous mRNA reporters, we show that the AU-rich element-containing 3 ′ untranslated region of Per2 is responsible for KSRP-dependent mRNA decay.”
Quote in the paperSubstantial claim - Findingown data
On a chow diet, fed and fasting hepatic TG levels are significantly reduced in Ksrp-/- mice compared with wild-type mice.
“On a chow diet (NCD), fed and fasting hepatic TG levels were signifi cantly reduced in Ksrp Ϫ / Ϫ mice compared with wild-type mice ( Fig. 1A ).”
Quote in the paperSubstantial claim - Findingown data
A phase shift (delayed by ~4 h) occurs in the oscillations of several core clock genes including Per1, Clock, Rev-erba, Bmal1 (moderate), and Dbp in Ksrp-/- livers.
“We also observed a phase shift (delayed by ف 4 h) in the oscillations of several core clock genes including Per1 , Clock , Rev-erba , Bmal1 (while the delay of Bmal1 was moderate), and Dbp (a direct target of CLOCK/BMAL1) in Ksrp Ϫ / Ϫ livers ( Fig. 2A ).”
Quote in the paperSubstantial claim - Findingown data
KSRP shows a diurnal expression with higher expression levels between ZT8 and ZT16.
“In addition, KSRP showed a diurnal expression with higher expression levels between ZT8 and ZT16 ( Fig. 2C ).”
Quote in the paperNot a substantial claim - Findingown data
Per2 mRNA levels are significantly elevated in Ksrp-/- livers compared with wild-type in the dark period.
“While the abundance of most canonical core clock genes was not affected, Per2 mRNA levels were signifi cantly elevated in Ksrp Ϫ / Ϫ livers compared with wildtype in the dark period ( Fig. 2A ).”
Quote in the paperSubstantial claim - Findingown data
PER2 protein levels in Ksrp-/- livers are increased in the light and dark periods.
“PER2 protein levels in Ksrp Ϫ / Ϫ livers were also increased in the light and dark periods ( Fig. 2B ) while the levels of CLOCK and BMALl were not altered ( Fig. 2C ).”
Quote in the paperSubstantial claim - Findingown data
KSRP ablation protects from diet-induced hepatic steatosis.
“These data indicate that KSRP ablation reduces hepatic and serum TG levels and protects from diet-induced hepatic steatosis.”
Quote in the paperSubstantial claim - Findingown data
Unlike in livers, Per2 mRNA levels are not altered in Ksrp-/- epididymal white adipose tissue (eWAT).
“Unlike that in the livers, Per2 mRNA levels were not altered in Ksrp Ϫ / Ϫ epididymal white adipose tissue (eWAT) ( Fig. 2D ).”
Quote in the paperNot a substantial claim - Findingown data
Per2 gene is upregulated in the livers of Ksrp−/− mice.
“At the molecular level, we found that Per2 gene is upregulated and diurnal expression of several core clock genes is phase shifted in the livers of Ksrp Ϫ / Ϫ mice.”
Quote in the paperSubstantial claim - Findingown data
Downregulation of Per2 restored expression of Srebp1c and Pparg in Ksrp−/− primary hepatocytes.
“We showed that downregulation of Per2 restored expression of Srebp1c and Pparg in Ksrp Ϫ / Ϫ primary hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
Expression of Acaca and Scd1 is decreased in Ksrp-/- hepatocytes compared with wild-type both 28 h and 32 h after Dex treatment.
“Expression of Acaca and Scd1 was decreased in Ksrp Ϫ / Ϫ hepatocytes compared with wild-type both 28 h and 32 h after Dex treatment.”
Quote in the paperSubstantial claim - Findingown data
hGB-Per2 669 mRNA displays a half-life of 3.6 h in wild-type MEFs.
“The mRNA with the distal fragment (hGB-Per2 669 ) displayed a half-life ( t 1/2 ) of 3.6 h ( Fig. 7B ) in wild-type MEFs.”
Quote in the paperSubstantial claim - Findingown data
Downregulation of Per2 restores expression of Acaca and Scd1 in Ksrp-/- hepatocytes.
“Importantly, downregulation of Per2 restored their expression in Ksrp Ϫ / Ϫ hepatocytes ( Fig. 8A ).”
Quote in the paperSubstantial claim - Findingown data
In Ksrp−/− hepatocytes, downregulating Per2 to a level similar to wild-type restored the phase delay in cycling of clock genes and TG levels.
“We showed that downregulation of Per2 in Ksrp Ϫ / Ϫ hepatocytes to a level similar to wild-type level restored the phase delay in cycling of clock genes and TG levels while 50% reduction of Per2 in wild-type cells did not alter clock gene expression and TG levels ( Fig. 5 and Fig. 8 ).”
Quote in the paperSubstantial claim - Findingown data
Intracellular TG levels are decreased in Ksrp-/- hepatocytes.
“TG levels were decreased in Ksrp Ϫ / Ϫ hepatocytes ( Fig. 8C ).”
Quote in the paperSubstantial claim - Findingown data
Per2 mRNA is enriched in the anti-KSRP immunoprecipitate of wild-type liver extracts compared with control or Ksrp-/- extracts.
“Per2 mRNA was enriched in the anti-KSRP immunoprecipitate of wild-type liver extracts compared with either a control immunoprecipitate of wild-type extracts or an anti-KSRP immunoprecipitate using Ksrp Ϫ / Ϫ extracts ( Fig. 6D ).”
Quote in the paperSubstantial claim - Findingown data
In the absence of KSRP, Per2 mRNA levels are elevated due to increased mRNA stability.
“We observed an elevation of Per2 mRNA levels due to increased mRNA stability in the absence of KSRP and demonstrated that AU2 is responsible for KSRP-dependent mRNA decay ( Fig. 7 ).”
Quote in the paperSubstantial claim - Findingown data
Decay of hGB-Per2 669 mRNA is impaired in Ksrp-/- MEFs.
“Importantly, decay of hGB-Per2 669 mRNA was impaired in Ksrp Ϫ / Ϫ MEFs ( Fig. 7B ).”
Quote in the paperSubstantial claim - Findingreasoning
KSRP-Per2 mRNA complex is not detected in eWAT.
“Consistent with this, KSRP-Per2 mRNA complex is not detected in eWAT.”
Quote in the paperSubstantial claim - Findingown data
Diurnal expression of several core clock genes is phase shifted in the livers of Ksrp−/− mice.
“At the molecular level, we found that Per2 gene is upregulated and diurnal expression of several core clock genes is phase shifted in the livers of Ksrp Ϫ / Ϫ mice.”
Quote in the paperSubstantial claim - Findingreasoning
The increase in SREBP1c upon Per2 knockdown is not able to increase Pparg, Acaca, Fasn, and Scd1 and TG levels to similar levels as in Ksrp−/− hepatocytes.
“Thus, the increase in SREBP1c upon Per2 knockdown is not able Pparg , Acacs , Fasn , and Scd1 ( Fig. 9E ) and TG levels ( Fig. 9F ) to similar levels to that of Ksrp Ϫ / Ϫ hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
AU2 is responsible for KSRP-dependent mRNA decay.
“We observed an elevation of Per2 mRNA levels due to increased mRNA stability in the absence of KSRP and demonstrated that AU2 is responsible for KSRP-dependent mRNA decay ( Fig. 7 ).”
Quote in the paperSubstantial claim - Findingown data
In wild-type cells, a 50% reduction of Per2 did not alter clock gene expression and TG levels.
“We showed that downregulation of Per2 in Ksrp Ϫ / Ϫ hepatocytes to a level similar to wild-type level restored the phase delay in cycling of clock genes and TG levels while 50% reduction of Per2 in wild-type cells did not alter clock gene expression and TG levels ( Fig. 5 and Fig. 8 ).”
Quote in the paperSubstantial claim - Findingown data
Ectopic expression of Per2 in wild-type hepatocytes reduced expression of Srebp1c and Pparg.
“Conversely, ectopic expression of Per2 in wild-type hepatocytes reduced expression of Srebp1c and Pparg .”
Quote in the paperSubstantial claim - Findingown data
Per2 mRNA stability is increased in Ksrp-/- hepatocytes compared with wild type.
“As shown in Fig. 6A , Per2 mRNA stability was increased in Ksrp Ϫ / Ϫ hepatocytes compared with wild type.”
Quote in the paperSubstantial claim - Findingreasoning
KSRP ablation causes a reduction in hepatic TG content.
“This study shows that KSRP ablation causes a reduction in hepatic TG content.”
Quote in the paperSubstantial claim - Findingown data
After Per2 knockdown, Per2 mRNA levels remain oscillating in wild-type and Ksrp−/− cells.
“Although we did not examine oscillation of remaining PER2 protein in wild-type and Ksrp Ϫ / Ϫ cells after the knockdown, Per2 mRNA levels remain oscillating ( Fig. 5 ).”
Quote in the paperNot a substantial claim - Findingreasoning
In Ksrp−/− livers, daily cycling of lipid metabolism genes is disrupted with either a phase shift or reduced expression of enzymes and master regulators such as Pparg and Srebp1c involved in de novo lipogenesis.
“Similar to the disturbance in liver clock, daily cycling of lipid metabolism genes is disrupted with either a phase shift or reduced expression of enzymes and master regulators, such as Pparg and Srebp1c , involved in de novo lipogenesis.”
Quote in the paperSubstantial claim - Findingown data
In KSRP-overexpressed cells, only the mRNA levels of Acaca, Fasn, and Scd1 and TG were increased.
“However, only the mRNA levels of Acaca , Fasn , and Scd1 and TG were increased in KSRP-overexpressed cells.”
Quote in the paperNot a substantial claim - Interpretationown data
KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability.
“These fi ndings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability .”
Quote in the paperSubstantial claim - Interpretationown data
Increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP.
“Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP.”
Quote in the paperSubstantial claim - Interpretationown data
The phase delay in oscillations of Rev-erba, Bmal1, and Per1 in Ksrp-/- hepatocytes is due to increased Per2 expression.
“These data suggest that the phase delay in oscillations of Rev-erba , Bmal1 , and Per1 in Ksrp Ϫ / Ϫ hepatocytes is indeed due to increased Per2 expression.”
Quote in the paperSubstantial claim - Interpretationown data
AU2 mediates KSRP-dependent decay of Per2 mRNA.
“mRNAs showed similar mRNA stability in Ksrp Ϫ / Ϫ MEFs ( Fig. 7C ) suggesting that AU2 mediates KSRP-dependent decay of Per2 mRNA.”
Quote in the paperSubstantial claim - Interpretationreasoning
The reduced TG content in the livers of Ksrp−/− mice is at least partly attributed to attenuated hepatic lipogenesis.
“These fi ndings demonstrate a role of de novo lipogenesis in contributing to hepatic steatosis and support our hypothesis that the reduced TG content in the livers of Ksrp Ϫ / Ϫ mice is at least partly attributed to attenuated hepatic lipogenesis.”
Quote in the paperSubstantial claim - Interpretationown data
KSRP negatively regulates Per2 expression.
“These results suggest that KSRP negatively regulates Per2 expression and PER2 downregulates the expression of lipogenic genes.”
Quote in the paperSubstantial claim - Interpretationown data
KSRP deficiency attenuates intracellular TG levels.
“Altogether, these results strongly suggest that KSRP defi ciency attenuates intracellular TG levels ( Fig. 9F ).”
Quote in the paperSubstantial claim - Interpretationown data
KSRP is a critical factor in governing hepatic lipid metabolism through regulation of circadian timing of lipogenic gene expression.
“These fi ndings suggest KSRP as a critical factor in governing hepatic lipid metabolism through regulation of circadian timing of lipogenic gene expression and as a potential therapeutic target to control hepatosteatosis.”
Quote in the paperSubstantial claim - Premisecitation
Mice with liver ablation of Acaca and Scd1 have reduced liver TG levels.
“Furthermore, genetic studies have also demonstrated that mice with liver ablation of Acaca and Scd1 have reduced liver TG levels ( 57,58 ).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [57] Mao, 2006, Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis, Proc. Natl. Acad. Sci. USA. source
- cites [58] Miyazaki, 2007, Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis, Cell Metab. source
- Interpretationown data
KSRP has a tissue-specific role in controlling Per2 mRNA stability.
“The effect of KSRP ablation on Per2 mRNA levels was only observed in the liver but not in eWAT, suggesting a tissue-specifi c role of KSRP in controlling Per2 mRNA stability.”
Quote in the paperSubstantial claim - Interpretationown data
KSRP promotes Per2 mRNA decay through the interaction with the AU2 region.
“Altogether, these data suggest that KSRP promotes Per2 mRNA decay through the interaction with the AU2 region.”
Quote in the paperSubstantial claim - Interpretationreasoning
KSRP plays a critical role in lipid metabolism through regulation of Per2 expression in the liver.
“These results suggest that increased expression of Per2 in Ksrp Ϫ / Ϫ hepatocytes results in downregulation of Pparg and Srebp1c , thereby reducing lipogenesis and TG content, and that KSRP plays a critical role in lipid metabolism through regulation of Per2 expression in the liver.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary hepatocytes of Ksrp−/− mice recapitulate the in vivo hepatic circadian and lipid phenotype.
- Interpretationown data
KSRP has a novel function in hepatic lipid metabolism.
“In summary, this work demonstrates a novel function of KSRP in hepatic lipid metabolism and suggests that reduction in hepatic de novo lipogenesis through modulation of KSRP activity could be a potential therapeutic target for hepatosteatosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary hepatocytes of Ksrp−/− mice recapitulate the in vivo hepatic circadian and lipid phenotype.
- Interpretationown data
The effects on cycling of clock genes and TG accumulation in Ksrp−/− cells are due to increased PER2.
“These fi ndings suggest that the remaining PER2 in wild-type cells is able to maintain normal oscillations of clock genes and that the effects on cycling of clock genes and TG accumulation in Ksrp Ϫ / Ϫ cells is indeed due to increased PER2.”
Quote in the paperSubstantial claim - Interpretationown data
PER2 downregulates the expression of lipogenic genes.
“These results suggest that KSRP negatively regulates Per2 expression and PER2 downregulates the expression of lipogenic genes.”
Quote in the paperSubstantial claim - Interpretationcitation
De novo lipogenesis contributes to hepatic steatosis.
“These fi ndings demonstrate a role of de novo lipogenesis in contributing to hepatic steatosis and support our hypothesis that the reduced TG content in the livers of Ksrp Ϫ / Ϫ mice is at least partly attributed to attenuated hepatic lipogenesis.”
Quote in the paperSubstantial claim - Interpretationown data
The remaining PER2 in wild-type cells is able to maintain normal oscillations of clock genes.
“These fi ndings suggest that the remaining PER2 in wild-type cells is able to maintain normal oscillations of clock genes and that the effects on cycling of clock genes and TG accumulation in Ksrp Ϫ / Ϫ cells is indeed due to increased PER2.”
Quote in the paperSubstantial claim- Rests on an assumption: Per2 mRNA oscillation reflects PER2 protein oscillation/levels in wild-type and Ksrp−/− cells after Per2 knockdown.
- The quote only partly states this claim. 1
- It may state two separate claims as one. 22
- Probably not a substantial claim. 8
The quote only partly states this claim.
Findingown dataKSRP ablation reduces serum TG levels.
“These data indicate that KSRP ablation reduces hepatic and serum TG levels and protects from diet-induced hepatic steatosis.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataExpression of genes involved in fatty acid synthesis (Acaca, Fasn, Scd1, Elovl6) and TG synthesis (Agpat2, Agpat6) either is decreased or shows a phase shift in the livers of Ksrp-/- mice.
“Expression of genes involved in fatty acid synthesis, including Acaca , Fasn , Scd1 , and Elovl6 , and TG synthesis, including Agpat2 and Agpat6 , either was decreased or showed a phase shift in the livers of Ksrp Ϫ / Ϫ mice ( Fig. 4A , B ), suggesting that either lipogenesis is attenuated or its timing is shifted.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataKnockdown of Per2 by siRNAs in Ksrp-/- hepatocytes restores the delayed phases of Rev-erba, Bmal1, and Per1 similar to wild-type hepatocytes, although downregulation of Per2 also decreases their levels.
“Knockdown of Per2 by siRNAs (siPer2) in Ksrp Ϫ / Ϫ hepatocytes restored the delayed phases of Rev-erba , Bmal1 , and Per1 similar to that of wild-type hepatocytes, although downregulation of Per2 also decreased their levels ( Fig. 5A ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn the SCN, Ksrp-/- mice show a moderate increase in expression of Per2 and Cry1 at ZT18 and Clock at ZT6, while expression of most clock genes is not affected.
“We examined the expression of clock genes in the SCN at the day time (ZT6) and the night time (ZT18) and observed a moderate increase in expression of Per2 and Cry1 at ZT18 and Clock at ZT6 in Ksrp Ϫ / Ϫ mice while expression of most clock genes was not affected ( Fig. 3C ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataOscillating phases of Rev-erba, Bmal1, and Per1 are delayed by 4 h in Ksrp-/- hepatocytes, although mRNA abundance is not altered.
“Oscillating phases of Rev-erba , Bmal1 , and Per1 were delayed by 4 h in Ksrp Ϫ / Ϫ hepatocytes, although the mRNA abundance was not altered ( Fig. 5A ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDownregulation of Per2 restores TG levels in Ksrp-/- hepatocytes to that of wild type, but does not affect TG levels in wild-type hepatocytes.
“Downregulation of Per2 restored TG levels in Ksrp Ϫ / Ϫ hepatocytes to that of wild type, but did not affect TG levels in wild-type hepatocytes ( Fig. 8C ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe effect of KSRP ablation on Per2 mRNA levels was observed in the liver but not in eWAT.
“The effect of KSRP ablation on Per2 mRNA levels was only observed in the liver but not in eWAT, suggesting a tissue-specifi c role of KSRP in controlling Per2 mRNA stability.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn primary hepatocytes of Ksrp−/− mice, downregulation of Per2 reverses the phase shift in oscillations of clock genes and restores the downregulation of lipogenic genes.
“Using primary hepatocytes of Ksrp Ϫ / Ϫ mice, we demonstrated that downregulation of Per2 reverses the phase shift in oscillations of clock genes and restores the downregulation of lipogenic genes.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataExpression of Cd36, Slc27a2, and Ldlr is either decreased or phase shifted in Ksrp−/− livers.
“However, we cannot exclude that reduced or altered fatty acid uptake also contributes a reduction in TG content as expression of Cd36 , Slc27a2 , and Ldlr is either decreased or phase shifted in Ksrp Ϫ / Ϫ livers ( Fig. 4C ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn wild-type cells, both Per2 knockdown and KSRP overexpression increased Srebp1c.
“We found that both Per2 knockdown and KSRP overexpression increased Srebp1c in wild-type cells ( Fig. 8B and Fig. 9C ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataMutations of AU1 and AU3 do not alter the decay rate compared with hGB-Per2 669 mRNA in wild-type MEFs, while mutation of AU2 impairs mRNA decay.
“While mutations of AU1 and AU3 did not alter the decay rate compared with hGB-Per2 669 mRNA in wild-type MEFs, mutation of AU2 impaired mRNA decay ( Fig. 7C ).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningThe reduction is particularly concentrated on genes encoding enzymes involved in de novo lipogenesis likely due to a reduction in expression of their upstream regulators such as Pparg and Srebp1c.
“The reduction is particularly concentrated on the genes encoding enzymes involved in de novo lipogenesis likely due to a reduction in expression of their upstream regulators such as Pparg and Srebp1c .”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataKSRP moderately regulates the central clock and is required for maintaining a normal circadian period.
“These results suggest that KSRP moderately regulates the central clock and is required for maintaining a normal circadian period.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataUpregulation of Per2 and phase shift in several circadian clock genes in Ksrp-/- livers are cell autonomous and unlikely due to changes in the behavior of Ksrp-/- mice.
“These data strongly implicate that upregulation of Per2 and phase shift in several circadian clock genes in Ksrp Ϫ / Ϫ livers are cell autonomous and unlikely due to changes in the behavior of Ksrp Ϫ / Ϫ mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataKSRP deficiency results in either phase shift in oscillations or reduced expression of several lipid metabolism genes in the liver.
“These data indicate that KSRP defi ciency results in either phase shift in oscillations or reduced expression of several lipid metabolism genes in the liver.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataKSRP targets Per2 mRNA for decay by an RNA-protein interaction and upregulation of Per2 is due to decreased mRNA decay in the absence of KSRP.
“These results suggest that KSRP targets Per2 mRNA for decay by an RNAprotein interaction and upregulation of Per2 is due to decreased mRNA decay in the absence of KSRP.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
InterpretationreasoningUpregulation of Per2 in Ksrp-/- liver may cause dysregulation or misalignment of the liver clock with feeding behavior and/or nutritional state resulting in altered accumulation of hepatic TG.
“The upregulation of Per2 in Ksrp Ϫ / Ϫ liver may cause dysregulation or misalignment of the liver clock with feeding behavior and/or nutritional state resulting in altered accumulation of hepatic TG.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationSREBP1c is a transcription factor that increases lipogenesis by promoting expression of lipogenic genes such as Acaca, Fasn, and Scd1.
“SREBP1c is a transcription factor that increases lipogenesis by promoting expression of lipogenic genes such as Acaca , Fasn , and Scd1 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [54] Ye, 2011, Regulation of cholesterol and fatty acid synthesis, Cold Spring Harb. Perspect. Biol. source
It may state two separate claims as one.
Interpretationown dataThe distal region of Per2 3' UTR directs mRNA decay and KSRP is responsible for the decay.
“These results suggest that the distal region of Per2 3 ′ UTR directs mRNA decay and KSRP is responsible for the decay.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationLiver-specific knockout of Pparg reduces expression of Acaca, Fasn, and Scd1 and hepatic steatosis.
“Whereas it is expressed mostly in adipose tissue, liver-specifi c knockout of Pparg reduces expression of Acaca , Fasn , and Scd1 and hepatic steatosis ( 55,56 ).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [55] Gavrilova, 2003, Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass, J. Biol. Chem. source
- cites [56] Matsusue, 2003, Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes, J. Clin. Invest. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDeficiency of hepatic SREBP1c fails to induce lipogenic gene expression.
“The critical role of SREBP1c in hepatic lipogenesis is supported by gain-and loss-of-function studies showing that overexpression of an active form develops steatosis as a result of elevation of lipogenesis, and conversely defi ciency of hepatic SREBP1c fails to induce lipogenic gene expression ( 54 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] Ye, 2011, Regulation of cholesterol and fatty acid synthesis, Cold Spring Harb. Perspect. Biol. source
It may state two separate claims as one.
InterpretationreasoningIncreased expression of Per2 in Ksrp−/− hepatocytes results in downregulation of Pparg and Srebp1c, thereby reducing lipogenesis and TG content.
“These results suggest that increased expression of Per2 in Ksrp Ϫ / Ϫ hepatocytes results in downregulation of Pparg and Srebp1c , thereby reducing lipogenesis and TG content, and that KSRP plays a critical role in lipid metabolism through regulation of Per2 expression in the liver.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPPARγ activates genes involved in lipid storage and metabolism.
“PPAR ␥ activates genes involved in lipid storage and metabolism.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [55] Gavrilova, 2003, Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass, J. Biol. Chem. source
- cites [56] Matsusue, 2003, Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes, J. Clin. Invest. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOverexpression of an active form of SREBP1c develops steatosis as a result of elevation of lipogenesis.
“The critical role of SREBP1c in hepatic lipogenesis is supported by gain-and loss-of-function studies showing that overexpression of an active form develops steatosis as a result of elevation of lipogenesis, and conversely defi ciency of hepatic SREBP1c fails to induce lipogenic gene expression ( 54 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] Ye, 2011, Regulation of cholesterol and fatty acid synthesis, Cold Spring Harb. Perspect. Biol. source
Probably not a substantial claim. It may state two separate claims as one.
InterpretationreasoningPER2 may regulate the circadian clock, which in turn regulates diurnal expression of lipid metabolism genes.
“In an indirect role, PER2 may regulate the circadian clock, which in turn regulates diurnal expression of lipid metabolism genes.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataPER2 negatively regulates Srebp1c and Pparg.
“These data implicate that PER2 negatively regulates Srebp1c and Pparg .”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationKSRP is found in apoB editing catalytic component 1 complex and pri-miRNA processing complex.
“However, targeting KSRP might also affect several other pathways as it is also found in apoB editing catalytic component 1 complex ( 63, 64 ) and pri-miRNA processing complex ( 35 ).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [63] Lellek, 2000, Purification and molecular cloning of a novel essential component of the apolipoprotein B mRNA editing enzyme-complex, J. Biol. Chem. source
- cites [64] Lellek, 2002, Reconstitution of mRNA editing in yeast using a Gal4-apoB-Gal80 fusion transcript as the selectable marker, J. Biol. Chem. source
- cites [35] Trabucchi, 2009, The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs, Nature. source
The paper relies on this without support.
Per2 mRNA oscillation reflects PER2 protein oscillation/levels in wild-type and Ksrp−/− cells after Per2 knockdown.
“Although we did not examine oscillation of remaining PER2 protein in wild-type and Ksrp Ϫ / Ϫ cells after the knockdown, Per2 mRNA levels remain oscillating ( Fig. 5 ).”
The paper relies on this without support.
Primary hepatocytes of Ksrp−/− mice recapitulate the in vivo hepatic circadian and lipid phenotype.
“Using primary hepatocytes of Ksrp Ϫ / Ϫ mice, we demonstrated that downregulation of Per2 reverses the phase shift in oscillations of clock genes and restores the downregulation of lipogenic genes.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
PER2-associated TG results cite the wrong Figure 9 panel
MinorThe text cites Figure 9F for TG levels compared with Ksrp-null hepatocytes, but the figure caption assigns that comparison to Figure 9G. Figure 9F instead shows TG levels after KSRP overexpression.
“TG levels ( Fig. 9F ) to similar levels to that of Ksrp Ϫ / Ϫ hepatocytes.”
“F and G: Intracellular TG levels in wild-type hepatocytes expressing Flag-KSRP (F) and in wild-type hepatocytes expressing Myc-PER2 and Ksrp Ϫ / Ϫ hepatocytes (G).”
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1371/journal.pbio.0050005
InfoThe cited work was retracted on 2015-11-16 (notice 10.1371/journal.pbio.1002314), not before this paper was published (2015-02).
Cited work 10.1371/journal.pbio.0050005 · retracted 2015-11-16 · notice 10.1371/journal.pbio.1002314 · this paper published 2015-02
“Gherzi, 2006, The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling, PLoS Biol., 5, e5, 10.1371/journal.pbio.0050005”
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CNOT1 regulates circadian behaviour through Per2 mRNA decay in a deadenylation-dependent manner
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COPS5 regulates osteosarcoma progression by upregulating KHSRP to promote Per2 mRNA decay
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Metadata
- Authors
- Chou, C.-F., Zhu, X., Lin, Y.-Y., Gamble, K. L., Garvey, W. T., & Chen, C.-Y.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Chen, Ching-Yi
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 56
- Issue
- 2
- Pages
- 227-240
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC4306678
- OpenAlex
- W1972473596
- Cited by
- 20
- References
- 64
- Citations by year
- 2025: 3 · 2024: 2 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 2 · 2017: 3 · 2016: 2 · 2015: 1
- FWCI
- 0.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM068758)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- KSRP, Per2, hepatic lipid metabolism, circadian clock, mRNA stability, AU-rich elements, 3' untranslated region, non-alcoholic fatty liver disease, hepatic steatosis, de novo lipogenesis, clock genes, RNA-protein interactions, triglycerides
- MeSH terms
- Animals, Cells, Cultured, Eating, Gene Expression Regulation, Liver, Male, Ribonucleoproteins, Trans-Activators, RNA-Binding Proteins, Mice, Knockout, Hepatocytes, Immunoprecipitation, Lipid Metabolism, Mice, Period Circadian Proteins, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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