Protein&Cell

2018 Vol. 9, No. 2

Mammalian carboxylesterases (EC 3.1.1.1) have been
demonstrated to hydrolyze endogenous esters and thioesters
including lipids. Recent studies have revealed the role of
carboxylesterases in lipid metabolism and their relevance
to metabolic diseases. To translate pre-clinical studies in
cellular and mouse models to humans, differences and
similarities of carboxylesterases between mice and human
need to be elucidated. Jihong Lian and colleagues review
current knowledge and research progression in the structure
and function of mouse and human carboxylesterases, with
emphasis on physiological roles of these enzymes in lipid
metabolism and human diseases.

Recollection

Dr. Yang Zhong: An explorer on the road forever

Fan Chen, Bao-Rong Lu, James C. Crabbe, Jia-yuan Zhao, Bo-jian Zhong, Yu-peng Geng, Yu-fang Zheng, Hong-yan Wang

2018, 9(2): 141-144. doi: 10.1007/s13238-017-0496-1

[Abstract](205) [PDF 996KB](1102)

Abstract:

Reviews

mTORC1 signaling in hepatic lipid metabolism

Jinbo Han, Yiguo Wang

2018, 9(2): 145-151. doi: 10.1007/s13238-017-0409-3

[Abstract](125) [PDF 445KB](2115)

Abstract:
The mechanistic target of rapamycin (mTOR) signaling pathway regulates many metabolic and physiological processes in different organs or tissues. Dysregulation of mTOR signaling has been implicated in many human diseases including obesity, diabetes, cancer, fatty liver diseases, and neuronal disorders. Here we review recent progress in understanding how mTORC1 (mTOR complex 1) signaling regulates lipid metabolism in the liver.

The dark side of browning

Kirstin A. Tamucci, Maria Namwanje, Lihong Fan, Li Qiang

2018, 9(2): 152-163. doi: 10.1007/s13238-017-0434-2

[Abstract](288) [PDF 562KB](1907)

Abstract:
The induction of brown-like adipocyte development in white adipose tissue (WAT) confers numerous metabolic benefits by decreasing adiposity and increasing energy expenditure. Therefore, WAT browning has gained considerable attention for its potential to reverse obesity and its associated co-morbidities. However, this perspective has been tainted by recent studies identifying the detrimental effects of inducing WAT browning. This review aims to highlight the adverse outcomes of both overactive and underactive browning activity, the harmful side effects of browning agents, as well as the molecular brake-switch system that has been proposed to regulate this process. Developing novel strategies that both sustain the metabolic improvements of WAT browning and attenuate the related adverse side effects is therefore essential for unlocking the therapeutic potential of browning agents in the treatment of metabolic diseases.

New insight into inter-organ crosstalk contributing to the pathogenesis of nonalcoholic fatty liver disease (NAFLD)

Zhang Xu, Xuetao Ji, Qian Wang, ZhongJohn Li

2018, 9(2): 164-177. doi: 10.1007/s13238-017-0436-0

[Abstract](317) [FullText HTML] (83) [PDF 769KB](1909)

Abstract:
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.

Carboxylesterases in lipid metabolism: from mouse to human

Lian Jihong, Nelson Randal, Lehner Richard

2018, 9(2): 178-195. doi: 10.1007/s13238-017-0437-z

[Abstract](148) [FullText HTML] (47) [PDF 3492KB](1710)

Abstract:
Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (over)expression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Structural and functional roles of ether lipids

John M. Dean, Irfan J. Lodhi

2018, 9(2): 196-206. doi: 10.1007/s13238-017-0423-5

[Abstract](305) [PDF 732KB](3614)

Abstract:
Ether lipids, such as plasmalogens, are peroxisomederived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochemical change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes. Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biology of ether lipids and their potential significance in human disorders, including neurological diseases, cancer, and metabolic disorders.

The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control

Ruo-Ran Wang, Ran Pan, Wenjing Zhang, Junfen Fu, Jiandie D. Lin, Zhuo-Xian Meng

2018, 9(2): 207-215. doi: 10.1007/s13238-017-0442-2

[Abstract](292) [PDF 747KB](1805)

Abstract:
Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWI/SNF chromatin-remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological signals. The ATP-dependent SWI/SNF chromatin-remodeling complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different metabolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

The emerging role and targetability of the TCA cycle in cancer metabolism

M. Anderson Nicole, Mucka Patrick, G. Kern Joseph, Feng Hui

2018, 9(2): 216-237. doi: 10.1007/s13238-017-0451-1

[Abstract](239) [FullText HTML] (52) [PDF 584KB](3525)

Abstract:
The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

Current Issue

November, 2021

Volume 12, Issue 11

Pages 825-902

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Ionizing radiation induces ACSL4-dependent lipid ROS to kill tumor cells through ferroptosis. Certain tumors exhibit strong defense systems to lipid ROS, for example, by upregulating SLC7A11 or GPX4 (as indicated by the shield held by soldiers), resulting in radioresistance. See our review for detailed discussion.

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2018 Vol. 9, No. 2

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