Effect of Fabp1/Scp‐2/Scp‐x Ablation on Whole Body and Hepatic Phenotype of Phytol‐Fed Male Mice

Landrock, Danilo; Milligan, Sherrelle; Martin, Gregory G.; McIntosh, Avery L.; Landrock, Kerstin K.; Schroeder, Friedhelm; Kier, Ann B.

doi:10.1007/s11745-017-4249-y

Cited by 9 publications

(11 citation statements)

References 82 publications

(158 reference statements)

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“…Taken together, these findings showed that the greater hepatic accumulation of phytanic acid in phytol-fed WT females than males correlated with the females' markedly lower expression of FABP1, SCP-2, and SCP-x than WT males (60,61), perhaps analogous to partial "knock-down" of these proteins involved in phytol metabolism. This possibility was supported by the finding that complete ablation of all three proteins (i.e., TKO) resulted in a much greater quantitative loss of FABP1, SCP-2, and SCP-x in male than female mice and, thereby correspondingly, in greater increase in phytanic acid accumulation in phytol-fed TKO males than their female counterparts.…”

Section: Tko Induces Hepatic Accumulation Of Phytol Metabolite Producmentioning

confidence: 73%

“…Because nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation, these studies suggested that the lower hepatic expression of FABP1, SCP-2, and SCP-x in WT females may make females more susceptible to NAFLD, correlating with high-fat-induced NAFLD in some strains of female (73), but not male, mice (74), as well as with the higher prevalence of NAFLD in women (74,75). Furthermore, phytol-diet made WT mice less susceptible to hepatic triacylglyceride accumulation, more so males than females and correlated with WT females having lower hepatic expression of FABP1, SCP-2, and SCP-x than WT males (60,61).…”

Section: Discussionmentioning

confidence: 95%

“…To begin to address this issue, the physiological impact of a 0.5% phytol-diet on whole body and hepatic phenotype has been examined in both WT mice and in mice ablated for all three proteins, i.e., Fabp1/Scp-2/Scp-x null (TKO). In WT mice, both whole body and hepatic lipid phenotype correlated with WT females' significantly lower expression of FABP1, SCP-2, and SCP-x than WT males (60,61). For example, despite similar food consumption, control-fed WT females had greater body weight gain and accumulated 3.4-fold more hepatic triacylglyceride than WT males (52).…”

Section: Discussionmentioning

confidence: 95%

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Impact of Fabp1/Scp-2/Scp-x gene ablation (TKO) on hepatic phytol metabolism in mice

Storey

Huang

McIntosh

et al. 2017

Journal of Lipid Research

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Studies in vitro have suggested that both sterol carrier protein-2/sterol carrier protein-x () and liver fatty acid binding protein [ (L-FABP)] gene products facilitate hepatic uptake and metabolism of lipotoxic dietary phytol. However, interpretation of physiological function in mice singly gene ablated in the has been complicated by concomitant upregulation of FABP1. The work presented herein provides several novel insights:) An 8-anilino-1-naphthalenesulfonic acid displacement assay showed that neither SCP-2 nor L-FABP bound phytol, but both had high affinity for its metabolite, phytanic acid; ) GC-MS studies with phytol-fed WT and gene ablated [triple KO (TKO)] mice showed that TKO exacerbated hepatic accumulation of phytol metabolites in vivo in females and less so in males. Concomitantly, dietary phytol increased hepatic levels of total long-chain fatty acids (LCFAs) in both male and female WT and TKO mice. Moreover, in both WT and TKO female mice, dietary phytol increased hepatic ratios of saturated/unsaturated and polyunsaturated/monounsaturated LCFAs, while decreasing the peroxidizability index. However, in male mice, dietary phytol selectively increased the saturated/unsaturated ratio only in TKO mice, while decreasing the peroxidizability index in both WT and TKO mice. These findings suggested that: ) SCP-2 and FABP1 both facilitated phytol metabolism after its conversion to phytanic acid; and) SCP-2/SCP-x had a greater impact on hepatic phytol metabolism than FABP1.

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Section: Tko Induces Hepatic Accumulation Of Phytol Metabolite Producmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

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Impact of Fabp1/Scp-2/Scp-x gene ablation (TKO) on hepatic phytol metabolism in mice

Storey

Huang

McIntosh

et al. 2017

Journal of Lipid Research

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“…iii) TKO results in different metabolic patterns between male and female mice due to sex differences in FABP1 and SCP-2/SCP-x expression as well as to Fabp1 and Scp2/Scp-x having different metabolic functions in health and disease. For example, phytol (a normal dietary constituent derived from the side chain of chlorophyll) markedly decreases body weight gain and increases weight loss more so in female than male WT mice [8,57,79]. This difference has been attributed to the lower expression of the protein products of the Fabp1 and/or Scp2/Scp-x genes, both of which are involved in phytol metabolism [5,8,75,107,113].…”

Section: Discussionmentioning

confidence: 99%

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Milligan

Martin

Landrock

et al. 2018

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

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Although singly ablating Fabp1 or Scp2/Scpx genes may exacerbate the impact of high fat diet (HFD) on whole body phenotype and non-alcoholic fatty liver disease (NAFLD), concomitant upregulation of the non-ablated gene, preference for ad libitum fed HFD, and sex differences complicate interpretation. Therefore, these issues were addressed in male and female mice ablated in both genes (Fabp1/Scp2/Scpx null or TKO) and pair-fed HFD. Wild-type (WT) males gained more body weight as fat tissue mass (FTM) and exhibited higher hepatic lipid accumulation than WT females. The greater hepatic lipid accumulation in WT males was associated with higher hepatic expression of enzymes in glyceride synthesis, higher hepatic bile acids, and upregulation of transporters involved in hepatic reuptake of serum bile acids. While TKO had little effect on whole body phenotype and hepatic bile acid accumulation in either sex, TKO increased hepatic accumulation of lipids in both, specifically phospholipid and cholesteryl esters in males and females and free cholesterol in females. TKO-induced increases in glycerides were attributed not only to complete loss of FABP1, SCP2 and SCPx, but also in part to sex-dependent upregulation of hepatic lipogenic enzymes. These data with WT and TKO mice pair-fed HFD indicate that: i) Sex significantly impacted the ability of HFD to increase body weight, induce hepatic lipid accumulation and increase hepatic bile acids; and ii) TKO exacerbated the HFD ability to induce hepatic lipid accumulation, regardless of sex, but did not significantly alter whole body phenotype in either sex.

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“…This mouse strain is available from The Jackson Laboratory (Item # 005304). TKO mice were developed as described (Landrock et al, ; Milligan et al, ; Storey et al, ). TKO mice have been deposited with and are available from The Jackson Laboratory (Bar Harbor, ME, USA).…”

Section: Methodsmentioning

confidence: 99%

Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

Martin

Seeger

McIntosh

et al. 2019

Lipids

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Brain endocannabinoids (EC) such as arachidonoylethanolamine (AEA) and 2‐arachidonoylglycerol (2‐AG) primarily originate from serum arachidonic acid (ARA), whose level is regulated in part by a cytosolic ARA‐binding protein, that is, liver fatty acid binding protein‐1 (FABP1), not expressed in the brain. Ablation of the Fabp1 gene (LKO) increases brain AEA and 2‐AG by decreasing hepatic uptake of ARA to increase serum ARA, thereby increasing ARA availability for uptake by the brain. The brain also expresses sterol carrier protein‐2 (SCP‐2), which is also a cytosolic ARA‐binding protein. To further resolve the role of SCP‐2 independent of FABP1, mice ablated in the Scp‐2/Scp‐x gene (DKO) were crossed with mice ablated in the Fabp1 gene (LKO) mice to generate triple knock out (TKO) mice. TKO impaired the ability of LKO to increase brain AEA and 2‐AG. While a high‐fat diet (HFD) alone increased brain AEA, TKO impaired this effect. Overall, these TKO‐induced blocks were not attributable to altered expression of brain proteins in ARA uptake, AEA/2‐AG synthesis, or AEA/2‐AG degrading enzymes. Instead, TKO reduced serum levels of free ARA and/or total ARA and thereby decreased ARA availability for uptake to the brain and downstream synthesis of AEA and 2‐AG therein. In summary, Scp‐2/Scp‐x gene ablation in Fabp1 null (LKO) mice antagonized the impact of LKO and HFD on brain ARA and, subsequently, EC levels. Thus, both FABP1 and SCP‐2 participate in regulating the EC system in the brain.

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Effect of Fabp1/Scp‐2/Scp‐x Ablation on Whole Body and Hepatic Phenotype of Phytol‐Fed Male Mice

Cited by 9 publications

References 82 publications

Impact of Fabp1/Scp-2/Scp-x gene ablation (TKO) on hepatic phytol metabolism in mice

Impact of Fabp1/Scp-2/Scp-x gene ablation (TKO) on hepatic phytol metabolism in mice

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

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