Glucagon regulates intracellular distribution of adipose differentiation-related protein during triacylglycerol accumulation in the liver

Takahashi, K.; Sasabe, Naoko; Ohshima, Kumiko; Kitazato, Keiko T.; Kato, Ryuichi; Masuda, Yutaka; Tsurumaki, Mika; Obama, Takashi; Okudaira, Shin Ichi; Aoki, Junken; Arai, Hiroyuki; Yamaguchi, Tomohiro; Itabe, Hiroyuki

doi:10.1194/jlr.m004648

Cited by 13 publications

(13 citation statements)

References 45 publications

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“…TG stored in liver in the form of cytosolic LDs increases massively after fasting because of FA influx into liver from adipose tissue [ 27 ]. Here we observed a significant reduction of flotillin-1 on LDs in the rat liver after fasting.…”

Section: Discussionmentioning

confidence: 99%

“…During fasting, rapid TG breakdown is initiated in other tissues (mainly adipose), thus increasing free fatty acid (FFA) in circulation. This FFA is delivered to the liver, where it is stored in the form of TG in LDs of hepatocytes, followed by release of TG into circulation in the form of lipoprotein (VLDL) particles [ 26 , 27 ]. These functions of the liver, namely storage and controlled release of TG, buffer other organs against lipotoxic effects of circulating FFA.…”

Section: Introductionmentioning

confidence: 99%

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Feeding-fasting dependent recruitment of membrane microdomain proteins to lipid droplets purified from the liver

2017

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Lipid droplets (LDs) are cellular stores of neutral fat that facilitate lipid and protein trafficking in response to metabolic cues. Unlike other vesicles, the phospholipid membrane on the LD is a monolayer. Interestingly, this monolayer membrane has free cholesterol, and may therefore contain lipid microdomains that serve as a platform for assembling proteins involved in signal transduction, cell polarity, pathogen entry etc. In support of this, cell culture studies have detected microdomain-associated “raftophilic” proteins on LDs. However, the physiological significance of this observation has been unclear. Here we show that two proteins (Flotillin-1 and SNAP23) that bind to membrane microdomains associate differently with LDs purified from rat liver depending on the feeding/fasting state of the animal. Flotillin-1 increases on LDs in the fed state, possibly because LDs interact with the endoplasmic reticulum (ER), facilitating supply of flotillin-1 from ER to LDs. Interestingly, this increase in flotillin-1 is correlated with an increase in free cholesterol on the LDs in fed state. In opposite behaviour to flotillin-1, SNAP23 increases on LDs in the fasted state and this appears to mediate LD-mitochondria interactions. Such LD-mitochondria interactions may provide fatty acids to mitochondria for promoting beta-oxidation in hepatocytes in response to fasting. Our work brings out physiologically relevant aspects of lipid droplet biology that are different from, and may not be entirely possible to replicate and study in cell culture.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Feeding-fasting dependent recruitment of membrane microdomain proteins to lipid droplets purified from the liver

2017

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“…However, this situation changes dramatically after fasting, when adipose-derived fatty acid reaches the liver and is esterified into TG in hepatocytes leading to massive accumulation of LD TG in the liver (∼4-fold increase; fasting induced steatosis). By sequestering away TG in this manner, the liver protects other organs from lipotoxic fatty acids ( 6 , 13 – 15 ).…”

mentioning

confidence: 99%

Kinesin-dependent mechanism for controlling triglyceride secretion from the liver

Rai

Kumar

Sharma

et al. 2017

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

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SignificanceThe liver secretes lipids in a controlled manner despite vast changes in its internal lipid content. This buffering function of the liver is essential for lipid/energy homeostasis, but its molecular and cellular mechanism is unknown. We show that motor protein kinesin transports lipid droplets (LDs) to the endoplasmic reticulum (ER) in liver cells, engineering ER−droplet contacts and supplying lipids to the ER for secretion as lipoprotein. However, when fasting induces massive lipid accumulation in liver, kinesin is removed from LDs, inhibiting lipid supply to the ER and homeostatically tempering lipid secretion from liver in a fasted state. Interestingly, reducing kinesin also blocks propagation of hepatitis-C virus inside liver cells, possibly because viral proteins cannot transfer from the ER to LDs.

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“…Perilipin 2 (PLIN2) is an LD-associated protein in the liver (48,54) and other tissues (6), and is the primary perilipin isoform that is strictly associated with LDs in liver (54). PLIN2 may inhibit intracellular TG lipolysis by blocking access of LDs to cytosolic lipases (5), and thus changes in its expression can possibly alter intracellular TG abundance and FA trafficking (35).…”

mentioning

confidence: 99%

Intensity-dependent and sex-specific alterations in hepatic triglyceride metabolism in mice following acute exercise

Tuazon

McConnell

Wilson

et al. 2015

Journal of Applied Physiology

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Precise regulation of hepatic triglyceride (TG) metabolism and secretion is critical for health, and exercise could play a significant role. We compared one session of high-intensity interval exercise (HIIE) vs. continuous exercise (CE) on hepatic TG metabolism. Female and male mice were assigned to CE, HIIE, or sedentary control (CON). HIIE was a 30-min session of 30-s running intervals (30 m/min) interspersed with 60-s walking periods (5 m/min). CE was a distance- and duration-matched run at 13.8 m/min. Hepatic content of TG and TG secretion rates, as well as expression of relevant genes/proteins, were measured at 3 h (day 1) and 28 h (day 2) postexercise. On day 1, hepatic [TG] in CE and HIIE were both elevated vs. CON in both sexes with an approximately twofold greater elevation in HIIE vs. CE in females. In both sexes, hepatic perilipin 2 (PLIN2) protein on day 1 was increased significantly by both exercise types with a significantly greater increase with HIIE than CE, whereas the increase in mRNA reached significance only after HIIE. On day 2 in both sexes the increases in hepatic TG and PLIN2 with exercise declined toward CON levels. Only HIIE on day 2 resulted in reduced hepatic TG secretion by ∼20% in females with no effect in males. Neither exercise modality altered AMPK signaling or microsomal triglyceride transfer protein expression. Females exhibited higher hepatic TG secretion than males in association with different expression levels of related metabolic enzymes. These intensity-dependent and sex-specific alterations following exercise may have implications for sex-based exercise prescription.

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Glucagon regulates intracellular distribution of adipose differentiation-related protein during triacylglycerol accumulation in the liver

Cited by 13 publications

References 45 publications

Feeding-fasting dependent recruitment of membrane microdomain proteins to lipid droplets purified from the liver

Feeding-fasting dependent recruitment of membrane microdomain proteins to lipid droplets purified from the liver

Kinesin-dependent mechanism for controlling triglyceride secretion from the liver

Intensity-dependent and sex-specific alterations in hepatic triglyceride metabolism in mice following acute exercise

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