Small Molecule-Induced Complement Factor D (Adipsin) Promotes Lipid Accumulation and Adipocyte Differentiation

Song, No Joon; Kim, Suji; Jang, Byung Hyun; Chang, Seok Woo; Yun, Ui Jeong; Park, Ki Moon; Waki, Hironori; Li, Dean Y.; Tontonoz, Peter; Park, Kye Won

doi:10.1371/journal.pone.0162228

Cited by 88 publications

(82 citation statements)

References 38 publications

(57 reference statements)

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“…Acylation-stimulating protein (ASP/C3adesArg), a downstream degradation product of C3, can stimulate triglyceride synthesis and glucose transport in adipocytes through the actions of the C3a receptor C5L2 (20,32). Indeed, FD is sufficient to induce the expression of PPAR␥, a transcription factor involved in assimilation of lipid, in preadipocytes (50). Modulation of the adipose-liver axis is one potential mechanism by which FD could protect from ethanol-induced steatosis.…”

Section: Discussionmentioning

confidence: 99%

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

McCullough

McMullen

Sheehan

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa, lacking classical pathway activation), complement protein 4-deficient ( C4, lacking classical and lectin pathway activation), complement factor D-deficient ( FD, lacking alternative pathway activation), and C1qa/FD (lacking classical and alternative pathway activation) mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 or 25 days. Following chronic ethanol exposure, liver injury, steatosis, and proinflammatory cytokine expression were increased in WT but not C1qa, C4, or C1qa/FD mice. In contrast, liver injury, steatosis, and proinflammatory mediators were robustly increased in ethanol-fed FD mice compared with WT mice. Complement activation, assessed by hepatic accumulation of C1q and complement protein 3 (C3) cleavage products (C3b/iC3b/C3c), was evident in livers of WT mice in response to both short-term and chronic ethanol. While C1q accumulated in ethanol-fed FD mice (short term and chronic), C3 cleavage products were detected after short-term but not chronic ethanol. Consistent with impaired complement activation, chronic ethanol induced the accumulation of apoptotic cells and fibrogenic responses in the liver of FD mice. These data highlight the protective role of complement factor D (FD) and suggest that FD-dependent amplification of complement is an adaptive response that promotes hepatic healing and recovery in response to chronic ethanol. NEW & NOTEWORTHY Complement, a component of the innate immune system, is an important pathophysiological contributor to ethanol-induced liver injury. We have identified a novel role for factor D, a component of the alternative pathway, in protecting the liver from ethanol-induced inflammation, accumulation of apoptotic hepatocytes, and profibrotic responses. These data indicate a dual role of complement with regard to inflammatory and protective responses and suggest that accumulation of apoptotic cells impairs hepatic healing/recovery during alcoholic liver disease.

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Section: Discussionmentioning

confidence: 99%

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

McCullough

McMullen

Sheehan

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…FD, which is also called adipsin, is a 25-kDa protein that is predominantly synthesized in differentiated adipocytes (11)(12)(13) and is required for AP activity (14,15). In addition, FD also serves important roles outside of complement, because it is involved in adipogenesis (16), insulin secretion (17), and obesity (13). FD is genetically encoded with a short hexameric propeptide (11), and the original report of FD purification also identified a minor zymogenic FD fraction that could be activated by trypsin (18).…”

mentioning

confidence: 99%

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

Pihl

Jensen

Hansen

et al. 2017

The Journal of Immunology

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Factor D (FD), which is also known as adipsin, is regarded as the first-acting protease of the alternative pathway (AP) of complement. It has been suggested that FD is secreted as a mature enzyme that does not require subsequent activation. This view was challenged when it was shown that mice lacking mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation. However, the necessity of MASP-3 for pro-FD cleavage has been questioned, because AP activity is still observed in sera from MASP-1/3-deficient Malpuech-Michels-Mingarelli-Carnevale (3MC) patients. The identification of a novel 3MC patient carrying a previously unidentified MASP-3 G665S mutation prompted us to develop an analytical isoelectric focusing technique that resolves endogenous FD variants in complex samples. This enabled us to show that although 3MC patients predominantly contain pro-FD, they also contain detectable levels of mature FD. Moreover, using isoelectric focusing analysis, we show that both pro-FD and FD are present in the circulation of healthy donors. We characterized the naturally occurring 3MC-associated MASP-3 mutants and found that they all yielded enzymatically inactive proteins. Using MASP-3-depleted human serum, serum from 3MC patients, and mice, we found that lack of enzymatically active MASP-3, or complete MASP-3 deficiency, compromises the conversion of pro-FD to FD. In summary, our observations emphasize that MASP-3 acts as an important maturase in the AP of complement, while also highlighting that there exists MASP-3-independent pro-FD maturation in 3MC patients.

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“…Adipsin is an adipokine secreted by adipocytes that promotes adipocyte differentiation. 59 While a potential role for adipsin as a catabolic mediator in joint tissues requires further investigation, it has been reported that levels of adipsin are higher in the serum 60 and cartilage 61 of OA patients compared to non-OA controls. Adiponectin is mainly produced in adipocytes and plays an important role in thermoregulation.…”

Section: Discussionmentioning

confidence: 99%

CITED2 mediates the mechanical loading–induced suppression of adipokines in the infrapatellar fat pad

Liu

et al. 2019

Annals of the New York Academy of Sciences

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Adipokines secreted from the infrapatellar fat pad (IPFP), such as adipsin and adiponectin, have been implicated in osteoarthritis pathogenesis. CITED2, a mechanosensitive transcriptional regulator with chondroprotective activity, may modulate their expression. Cited2 haploinsufficient mice (Cited2+/−) on a high‐fat diet (HFD) exhibited increased body weight and increased IPFP area compared to wild‐type (WT) mice on an HFD. While an exercise regimen of moderate treadmill running induced the expression of CITED2, as well as PGC‐1α, and reduced the expression of adipsin and adiponectin in the IPFP of WT mice on an HFD, Cited2 haploinsufficiency abolished the loading‐induced expression of PGC‐1α and loading‐induced suppression of adipsin and adiponectin. Furthermore, knocking down or knocking out CITED2 in adipose stem cells (ASCs)/preadipocytes derived from the IPFP in vitro led to the increased expression of adipsin and adiponectin and reduced PGC‐1α, and abolished the loading‐induced suppression of adipsin and adiponectin and loading‐induced expression of PGC‐1α. Overexpression of PGC‐1α in these ASC/preadipocytes reversed the effects caused by CITED2 deficiency. The current data suggest that CITED2 is a critical regulator in physiologic loading‐induced chondroprotection in the context of an HFD and PGC‐1α is required for the inhibitory effects of CITED2 on the expression of adipokines such as adipsin and adiponectin in the IPFP.

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Small Molecule-Induced Complement Factor D (Adipsin) Promotes Lipid Accumulation and Adipocyte Differentiation

Cited by 88 publications

References 38 publications

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

Complement Factor D protects mice from ethanol-induced inflammation and liver injury

Analysis of Factor D Isoforms in Malpuech–Michels–Mingarelli–Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement

CITED2 mediates the mechanical loading–induced suppression of adipokines in the infrapatellar fat pad

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