Hepatic Fatty Acid Trafficking: Multiple Forks in the Road

Mashek, Douglas G.

doi:10.3945/an.113.004648

Cited by 123 publications

(104 citation statements)

References 232 publications

(238 reference statements)

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“…infection mouse model. This is consistent with the known critical role of the liver in uptake of free fatty acids, fatty acid metabolism, and lipid trafficking including the assembly of very low density lipoprotein (34). Furthermore, pulmonary surfactant, which also contains an array of host-derived fatty acids, may play a role in tissue-specific activation of T7SS genes in host lungs (10), suggesting that this mechanism may be relevant in S. aureus pneumonia as well.…”

Section: Discussionsupporting

confidence: 84%

Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

Lopez¹,

Tan²,

Yan³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The type VII secretion system (T7SS) of Staphylococcus aureus is a multiprotein complex dedicated to the export of several virulence factors during host infection. This virulence pathway plays a key role in promoting bacterial survival and the long-term persistence of staphylococcal abscess communities. The expression of the T7SS is activated by bacterial interaction with host tissues including blood serum, nasal secretions, and pulmonary surfactant. In this work we identify the major stimulatory factors as host-specific cisunsaturated fatty acids. Increased T7SS expression requires host fatty acid incorporation into bacterial biosynthetic pathways by the S. aureus fatty acid kinase (FAK) complex, and FakA is required for virulence. The incorporated cis-unsaturated fatty acids decrease S. aureus membrane fluidity, and these altered membrane dynamics are partially responsible for T7SS activation. These data define a molecular mechanism by which S. aureus cells sense the host environment and implement appropriate virulence pathways.type VII secretion | Staphylococcus aureus | fatty acids | virulence

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Section: Discussionsupporting

confidence: 84%

Host-derived fatty acids activate type VII secretion inStaphylococcus aureus

Lopez¹,

Tan²,

Yan³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In the liver, it is thought that the primary source of TAG is via the glycerol-3-phosphate (G3P) pathway, that generates DAG (Coleman and Mashek 2011; Mashek 2013) which serves as a substrate of DAG transferases 1 and 2 (Dgat1/2). However, it is becoming evident that the MAG pathway [ie.…”

Section: Resultsmentioning

confidence: 99%

“…However, it is becoming evident that the MAG pathway [ie. generation of DAG from MAG via MAG transferases 1 and 2 (Mogat1/2 in mice)], may be a relevant pathway in NAFLD (Hall, et al 2012; Mashek 2013). Examination of the expression of key genes involved in TAG synthesis revealed there was an overall inhibitory effect of aLivPPARγkd on the expression of Mogat1 (Supplemental Table 1) that reached significance with age and HF feeding (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice

Greenstein

Majumdar

Yang

et al. 2017

Journal of Endocrinology

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Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. Since these hepatocyte-specific effects of PPARγ could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPARγ knockdown (aLivPPARγkd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPARγ on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPARγkd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18wks (Chow-fed) or after 14wks of low- or high-fat [HF] diet. aLivPPARγkd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPARγkd reduced the expression of the FA translocase (Cd36), in 18wk-Chow and HF-fed mice, associated with increased NEFA after HF-feeding. Also, aLivPPARγkd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPARγ, where loss of this control explains in part the protection against steatosis observed after aLivPPARγkd.

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“…Previous studies found that both Pu-erh tea and theabrownin suppressed lipid accumulation and slowed the rate of fatty degeneration in liver tissues [18,28]. The uptake of free fatty acids from the diet has been reported as one of the primary sources of liver-derived fatty acids [32]. In this study, we observed that the expression levels of several genes involved in fatty acid synthesis, such as pparα, pparγ, ampk, srebp1 and acc, were significantly decreased in the OTP group compared with the HFD group (Fig.…”

Section: Discussionmentioning

confidence: 98%