Knockdown of phosphatase and tensin homolog (PTEN) inhibits fatty acid oxidation and reduces very low density lipoprotein assembly and secretion in calf hepatocytes

Zhao, Bi-Chen; Luo, Chen; Zhang, Menglong; Xing, Feifei; Luo, Shengbin; Fu, Shixin; Sun, Xudong

doi:10.3168/jds.2019-17920

Cited by 10 publications

(8 citation statements)

References 44 publications

(50 reference statements)

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“…Our data revealed that high NEFA inhibited mRNA expressions of MTP, ApoB100, and ApoE, and thus suppressed the secretion of VLDL into the supernatants. The result was in line with previous studies [ 10 , 20 , 26 ]. Those data together support a central role of high NEFA in the TAG accumulation in hepatocytes and further in the initiation and progress of fatty liver in cows, highlighting a feasibility of treating or preventing fatty liver by blocking the detrimental effects of excessive NEFA.…”

Section: Discussionsupporting

confidence: 93%

Sirtuin 3 Restores Synthesis and Secretion of Very Low-Density Lipoproteins in Cow Hepatocytes Challenged with Nonesterified Fatty Acids In Vitro

Xing

Wang

Lü

et al. 2021

Veterinary Sciences

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Fatty liver is closely associated with elevated concentrations of nonesterified fatty acids (NEFA) and a low level of very low-density lipoproteins (VLDL) in blood of dairy cows. High NEFA inhibit the VLDL synthesis and assembly, and cause hepatic triacylglycerol (TAG) deposition. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, antagonizes NEFA-induced TAG accumulation through modulating expressions of fatty acid synthesis and oxidation genes in cow hepatocytes. However, the role of SIRT3 in the VLDL synthesis and assembly was largely unknown. Here we aimed to test whether SIRT3 would recover the synthesis and assembly of VLDL in cow hepatocytes induced by high NEFA. Primary cow hepatocytes were isolated from 3 Holstein cows. Hepatocytes were infected with SIRT3 overexpression adenovirus (Ad-SIRT3), SIRT3-short interfering (si) RNA, or first infected with Ad-SIRT3 and then incubated with 1.0 mM NEFA (Ad-SIRT3 + NEFA). Expressions of key genes in VLDL synthesis and the VLDL contents in cell culture supernatants were measured. SIRT3 overexpression significantly increased the mRNA abundance of microsomal triglyceride transfer protein (MTP), apolipoprotein B100 (ApoB100) and ApoE (p < 0.01), and raised VLDL contents in the supernatants (p < 0.01). However, SIRT3 silencing displayed a reverse effect in comparison to SIRT3 overexpression. Compared with NEFA treatment alone, the Ad-SIRT3 + NEFA significantly upregulated the mRNA abundance of MTP, ApoB100 and ApoE (p < 0.01), and increased VLDL contents in the supernatants (p < 0.01). Our data demonstrated that SIRT3 restored the synthesis and assembly of VLDL in cow hepatocytes challenged with NEFA, providing an in vitro basis for further investigations testing its feasibility against hepatic TAG accumulation in dairy cows during the perinatal period.

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Section: Discussionsupporting

confidence: 93%

Sirtuin 3 Restores Synthesis and Secretion of Very Low-Density Lipoproteins in Cow Hepatocytes Challenged with Nonesterified Fatty Acids In Vitro

Xing

Wang

Lü

et al. 2021

Veterinary Sciences

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“…Fatty acid oxidation is a key biological process within the liver that helps regulate not only energy availability to liver cells, but also water-soluble fuels in the form of ketone bodies that peripheral tissues can use (Zhao et al, 2020). Activity of CPT1A regulates the entry of fatty acids into mitochondria before entry into β-oxidation (Li et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Role of diacylglycerol O-acyltransferase (DGAT) isoforms in bovine hepatic fatty acid metabolism

Yang

Wang

Loor

et al. 2022

Journal of Dairy Science

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Fatty acid accumulation in hepatocytes induced by high concentrations of fatty acids due to lipolysis and the associated oxidative damage they cause occur most frequently after calving. Because of their role in esterification of fatty acids, diacylglycerol acyltransferase isoforms (DGAT1 and DGAT2) could play a role in the susceptibility of dairy cows to develop fatty liver. To gain mechanistic insights, we performed in vivo and in vitro analyses using liver biopsies or isolated primary hepatocytes. The in vivo study (n = 5 cows/group) involved healthy cows [average liver triacylglycerol (TAG) = 0.78%; 0.58 to 0.93%, ratio of triglyceride weight to wet liver weight] or cows diagnosed with fatty liver (average TAG = 7.60%; 5.31 to 10.54%). In vitro, hepatocytes isolated from 3 healthy female calves (1 d old, 44 to 53 kg) were challenged with (fatty acids) or without (control) a 1.2 mM mixture of fatty acids in an attempt to induce metabolic stress. Furthermore, hepatocytes were treated with DGAT1 inhibitor or DGAT2 inhibitor for 2 h followed by a challenge with (DGAT1 inhibitor + fatty acids or DGAT2 inhibitor + fatty acids) or without (DGAT1 inhibitor or DGAT2 inhibitor) the 1.2 mM mixture of fatty acids for 12 h. Data analysis of liver biopsies was compared using a 2-tailed unpaired Student's t-test. Data from calf hepatocyte treatment comparisons were assessed by one-way ANOVA, and multiplicity for each experiment was adjusted by the Holm's procedure. Data indicated that both fatty liver and in vitro challenge with fatty acids were associated with greater mRNA and protein abundance of SREBF1, FASN, DGAT1, and DGAT2. In contrast, mRNA and protein abundance of CPT1A and very low-density lipoprotein synthesis-related proteins MTTP and APOB were markedly lower. However, compared with fatty acid challenge alone, DGAT1 inhibitor + fatty acids led to greater mRNA and protein abundance of CPT1A and APOB, and greater mRNA abundance of SREBF1 and MTTP. Furthermore, this treatment led to lower mRNA abundance of FASN and DGAT2 and TAG concentrations. Compared with fatty acid challenge alone, DGAT2 inhibitor + fatty acids led to greater mRNA and protein abundance of CPT1A, MTTP, and APOB, and lower mRNA and protein abundance of SREBF1 and FASN. In addition, compared with control and fatty acids, there was greater protein abundance of GRP78 and PERK in both DGAT1 and DGAT2 inhibitor with or without fatty acids. Furthermore, compared with control and fatty acids, reactive oxygen species concentrations in the DGAT1 inhibitor with or without fatty acid group was greater. Overall, data suggested that DGAT1 is particularly relevant in the context of hepatocyte TAG synthesis from exogenous fatty acids. Disruption of both DGAT1 and DGAT2 altered lipid homeostasis, channeling fatty acids toward oxidation and generation of reactive oxygen species. Both DGAT isoforms play a role in promoting fatty acid storage into TAG and lipid droplets to protect hepatocytes from oxidative damage.

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“…PTEN functions as the most critical inhibitor of the PI3K pathway. Surprisingly, both PTEN inhibition and expression inhibit β‐oxidation, most likely via two different mechanisms; one mechanism is dependent on the PI3K/AKT pathway, and the other is independent 47,48 . The mechanism of the latter remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, both PTEN inhibition and expression inhibit β-oxidation, most likely via two different mechanisms; one mechanism is dependent on the PI3K/AKT pathway, and the other is independent. 47,48 The mechanism of the latter remains unknown. On the one hand, functions associating with PTEN nuclear localization might explain the underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

Wen

Jiao

et al. 2022

Clinical & Translational Med

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Background & aims Transient regeneration–associated steatosis (TRAS) is a process of temporary hepatic lipid accumulation and is essential for liver regeneration by providing energy generated from fatty acid β‐oxidation, but the regulatory mechanism underlying TRAS remains unknown. Parkinsonism‐associated deglycase (Park7)/Dj1 is an important regulator involved in various liver diseases. In nonalcoholic fatty liver diseased mice, induced by a high‐fat diet, Park7 deficiency improves hepatic steatosis, but its role in liver regeneration remains unknown Methods Park7 knockout (Park7−/−), hepatocyte‐specific Park7 knockout (Park7△hep) and hepatocyte‐specific Park7‐Pten double knockout mice were subjected to 2/3 partial hepatectomy (PHx) Results Increased PARK7 expression was observed in the regenerating liver of mice at 36 and 48 h after PHx. Park7−/− and Park7△hep mice showed delayed liver regeneration and enhanced TRAS after PHx. PPARa, a key regulator of β‐oxidation, and carnitine palmitoyltransferase 1a (CPT1a), a rate‐limiting enzyme of β‐oxidation, had substantially decreased expression in the regenerating liver of Park7△hep mice. Increased phosphatase and tensin homolog (PTEN) expression was observed in the liver of Park7△hep mice, which might contribute to delayed liver regeneration in these mice because genomic depletion or pharmacological inhibition of PTEN restored the delayed liver regeneration by reversing the downregulation of PPARa and CPT1a and in turn accelerating the utilization of TRAS in the regenerating liver of Park7△hep mice Conclusion Park7/Dj1 is a novel regulator of PTEN‐dependent fatty acid β‐oxidation, and increasing Park7 expression might be a promising strategy to promote liver regeneration.

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Knockdown of phosphatase and tensin homolog (PTEN) inhibits fatty acid oxidation and reduces very low density lipoprotein assembly and secretion in calf hepatocytes

Cited by 10 publications

References 44 publications

Sirtuin 3 Restores Synthesis and Secretion of Very Low-Density Lipoproteins in Cow Hepatocytes Challenged with Nonesterified Fatty Acids In Vitro

Sirtuin 3 Restores Synthesis and Secretion of Very Low-Density Lipoproteins in Cow Hepatocytes Challenged with Nonesterified Fatty Acids In Vitro

Role of diacylglycerol O-acyltransferase (DGAT) isoforms in bovine hepatic fatty acid metabolism

PARK7 deficiency inhibits fatty acid β‐oxidation via PTEN to delay liver regeneration after hepatectomy

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