Leptin Enhances Hepatic Fibrosis and Inflammation in a Mouse Model of Cholestasis

Petrescu, Anca D.; Grant, Stephanie; Williams, Elaina; An, Su Yeon; Seth, Nikhil; Shell, Mark S. La; Amundsen, Tyson; Tan, Christopher; Nadeem, Yusra; Tjahja, Matthew; Weld, Lancaster; Chu, Christopher; Venter, Julie; Frampton, Gabriel; McMillin, Matthew; DeMorrow, Sharon

doi:10.1016/j.ajpath.2021.11.008

Cited by 14 publications

(9 citation statements)

References 50 publications

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“…Circulating LEP levels are proportionally correlated with fat mass, and obese individuals have higher levels of LEP but no anorexic response, a phenomenon known as leptin resistance [ 20 ]. Furthermore, LEP has pro-inflammatory activity, and its elevated levels are associated with insulin resistance and liver fibrosis in obese individuals [ 21 ]. To date, ADPN is an adipokine that is negatively associated with obesity, but its levels are higher in healthy people who have gained weight and are lower in a metabolically disturbed state of obesity.…”

Section: Discussionmentioning

confidence: 99%

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

et al. 2022

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Obesity has become a global epidemic disease as it is closely associated with a chronic low-grade inflammatory state that results in metabolic dysfunction. Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from Morus alba L. were licensed to treat type 2 diabetes (T2DM) in 2020. In this study, we explored the effect of SZ-A on adipose tissue metabolism and inflammation using an obesity model induced by a high-fat diet (HFD). C57BL/6J mice were fed high fat for 14 weeks and followed by SZ-A 400 mg/kg treatment via gavage for another six weeks, during which they were still given the high-fat diet. The results showed that SZ-A notably reduced body weight and serum levels of lipid metabolism-related factors, such as triglycerides (TG) and total cholesterol (TC); and inflammation-related factors, namely tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), fibrinogen activator inhibitor-1 (PAI-1), angiopoietin-2 (Ang-2), and leptin (LEP), in the HFD-induced mice. SZ-A increased the protein and mRNA expression of lipid metabolism-related factors, including phosphorylated acetyl coenzyme A carboxylase (p-ACC), phosphorylated hormone-sensitive triglyceride lipase (p-HSL), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-alpha (PPARα), in adipose tissue. Immunohistochemistry results demonstrated that SZ-A significantly reduced the infiltration of pro-inflammatory M1-type macrophages in epididymal fat. The data also suggested that SZ-A down-regulates the transcriptional levels of inflammatory factors Il6, Tnfα, monocyte chemoattractant protein-1 (Mcp1), and F4/80, and up-regulates interleukin 4 (Il4), interleukin 10 (Il10), and interleukin 13 (Il13) in adipose tissue. Overall, the results indicate that SZ-A exhibits potential in regulating lipid metabolism and ameliorating obesity-linked adipose inflammation.

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Section: Discussionmentioning

confidence: 99%

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

et al. 2022

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“…Leptin has been shown to modulate the fibroblastic and inflammatory processes of hepatic cholestasis, hepatic fibrosis, and chronic allergic airway disease [ 26 , 27 , 28 ]. Type II diabetic patients have been shown to have a lower serum leptin level and are prone to suffer from SS [ 14 , 15 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of Leptin among Patients with Shoulder Stiffness

Chen

et al. 2022

Life

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Shoulder stiffness (SS) is a disease that is fibroblastic and inflammatory in nature. Leptin is an adipokine-mediating the fibroblastic and inflammatory processes of various diseases. Our study tried to investigate the role of leptin in SS pathogenesis. Subacromial bursa from stiff and non-stiff shoulders were obtained for reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunoblotting. Subacromial fluid was obtained for enzyme-linked immunosorbent assay. We showed that the expression level of leptin was lower in the subacromial bursae from the stiff shoulders in RT-PCR analysis (p < 0.001) and immunoblotting (p < 0.001). The concentration of leptin was also lower in the subacromial fluid derived from stiff shoulders. The leptin level in the subacromial fluid was positively associated with the constant score, total range of motion, flexion, abduction, and external rotation. The synovial fibroblasts derived from stiff shoulder-retrieved subacromial bursa were treated by 0, 1, and 3 μM leptin. Under RT-qPCR analysis, leptin was shown to dose-dependently decrease the transcription of IL-6, IL-10, and IL-13, but without impact on IL-1β and IL-4 (p < 0.001, p = 0.001, p = 0.001, p = 0.137, and p = 0.883 by ANOVA test, respectively). These results shed light on the role of leptin in orchestrating the disease processes of SS.

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“…A study based on US population data revealed that serum leptin concentration is considerably elevated in NAFLD patients, and the leptin concentration is positively associated with the severity of NAFLD [110]. The ability of leptin to promote hepatic inflammation by upregulating the expressions of CCL2 and IL-6 and induce hepatic fibrosis by the activation of HSC has been demonstrated in a cholestasis mouse model [111]. Adipokine dyshomeostasis contributes to the progression of NAFLD by advancing hepatic inflammation and fibrosis.…”

Section: Adipose Tissue Dysfunction For Nafld Progressionmentioning

confidence: 99%

“…Lactobacillus probiotic bacteria are capable of restoring the blood serum adipokine levels in obese mice by increasing the adiponectin level and decreasing the leptin level [158]. Adiponectin deficiency and leptin overexpression can promote hepatic steatosis by restricting FA β-oxidation and facilitate the steatosis progression to NASH by advancing hepatic inflammation [76,111].…”

mentioning

confidence: 99%

Proanthocyanidins-Based Synbiotics as a Novel Strategy for Nonalcoholic Fatty Liver Disease (NAFLD) Risk Reduction

Thilakarathna,

Rupasinghe

2024

Molecules

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Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, is a spectrum of liver abnormalities ranging from steatosis to nonalcoholic steatohepatitis (NASH) characterized by excessive lipid accumulation. The prevalence of NAFLD is predicted to increase rapidly, demanding novel approaches to reduce the global NAFLD burden. Flavonoids, the most abundant dietary polyphenols, can reduce the risk of NAFLD. The majority of dietary flavonoids are proanthocyanidins (PACs), which are oligomers and polymers of the flavonoid sub-group flavan-3-ols. The efficacy of PAC in reducing the NAFLD risk can be significantly hindered by low bioavailability. The development of synbiotics by combining PAC with probiotics may increase effectiveness against NAFLD by biotransforming PAC into bioavailable metabolites. PAC and probiotic bacteria are capable of mitigating steatosis primarily through suppressing de novo lipogenesis and promoting fatty acid β-oxidation. PAC and probiotic bacteria can reduce the progression of steatosis to NASH mainly through ameliorating hepatic damage and inflammation induced by hepatic oxidative stress, endoplasmic reticulum stress, and gut microbiota dysbiosis. Synbiotics of PAC are superior in reducing the risk of NAFLD compared to independent administration of PAC and probiotics. The development of PAC-based synbiotics can be a novel strategy to mitigate the increasing incidence of NAFLD.

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Leptin Enhances Hepatic Fibrosis and Inflammation in a Mouse Model of Cholestasis

Cited by 14 publications

References 50 publications

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

Decreased Expression of Leptin among Patients with Shoulder Stiffness

Proanthocyanidins-Based Synbiotics as a Novel Strategy for Nonalcoholic Fatty Liver Disease (NAFLD) Risk Reduction

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