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研究生：	簡世杰 Chien, Shih-Chieh
論文名稱：	小異二聚體伴侶在代謝異常脂肪性肝病所扮演獨特的角色 Distinct role of nuclear-localized small heterodimer partner in metabolic dysfunction-associated steatohepatitis
指導教授：	蔡曜聲 Tsai, Yau-Sheng 陳炯瑜 Chen, Chiung-Yu
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2026
畢業學年度：	114
語文別：	英文
論文頁數：	74
中文關鍵詞：	代謝功能異常相關脂肪性肝炎、膽酸、小異二聚體伴侶、核因子 NFκB 、非典型細胞激素C zeta
外文關鍵詞：	Metabolic-dysfunction associated steatohepatitis, bile acids, small heterodimer partner, nuclear factor kappa B, protein kinase C zeta
相關次數：	點閱：72 下載：0
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核因子小異二聚體伴侶(SHP)具有維持膽酸恆定及抗發炎的雙重功能。雖然SHP被認為與代謝異常性脂肪性肝病(MASLD)有關，但其在病人身上扮演的角色仍不清楚。
我們在臨床上收集了79位受試者的肝臟組織與血液，包含69位代謝異常性脂肪性肝炎(MASH)的病人與10位正常的受試者。其中有33位同時包含有糞便的檢體。所有血液及糞便檢體皆接受膽酸的分析。而他們的肝組織則用來染色並分析SHP與相關蛋白在肝組織內的分布情形，並且將之與MASH有關的病理及臨床特徵(包含膽酸)做相關性分析。利用細胞實驗，我們闡述在MASH病人肝內所觀察到的相關致病機轉與其臨床上所代表的意義。
分析結果顯示，MASH病人的肝組織與正常人比起來，其肝細胞SHP入核程度呈現顯著的增加 (MASH病人: 51.7% vs. 正常人: 1.55%, p值 < 0.001) ，而其入核比率與肝臟脂肪累積程度及發炎程度呈顯著正相關，但與血液膽酸濃度無關。肝細胞內SHP的入核程度伴隨著非典型細胞激素C zeta (protein kinase C zeta, PKCζ)的訊號強度增強而增加，並且與核孔蛋白RanBP2的入核程度高度重疊。細胞實驗顯示，毒性脂肪酸與發炎激素皆會誘導SHP入核，並會因PKCζ的活性被抑制而阻斷。SHP的基因敲落( knockdown) 會導致基礎先天免疫(innate immunity)反應增強，加速細胞內的脂肪堆積，並且重現類似 MASH 病人肝內所觀察到的促進膽酸累積的基因表現型。進一步研究顯示SHP與下游抑制膽酸的共同抑制因子LSD1的蛋白結合力會因為發炎激素的刺激而減弱，但其與發炎因子IκB的結合程度會被保留而不會減弱。
我們的研究發現核因子SHP在肝細胞核內的堆積是MASH病人肝臟病理的一個特徵。這個現象與非典型細胞激素PKCζ的活性有關，其可能的目的是去減少MASH病人的發炎及避免膽酸的累積。

Background and Aims: The nuclear receptor small heterodimer partner (SHP) plays essential roles in regulating bile-acid (BA) homeostasis and limiting hepatic inflammatory responses. Although SHP has been implicated in the pathophysiology of metabolic dysfunction–associated steatohepatitis (MASH), its functional significance in human MASH remains unclear. This study aimed to characterize SHP regulation in patients with MASH and to delineate the mechanisms underlying its nuclear translocation.
Methods: Liver tissue, serum, and fecal samples were obtained from 69 patients with MASH and 10 healthy controls. Serum BA compositions in the participants were quantified, and the subcellular localization of SHP and related proteins in liver tissue was assessed in relation to MASH-associated pathological features. Complementary in vitro experiments were performed to elucidate the mechanism and biological relevance of SHP nuclear translocation in MASH.
Results: Relative to controls, individuals with MASH exhibited a markedly elevated nuclear SHP ratio (51.7% vs. 1.55%, p < 0.001), which correlated with the severity of steatosis and hepatitis but showed no association with serum BA concentrations. The nuclear SHP ratio increased in parallel with atypical protein kinase C zeta (PKCζ) signal intensity and demonstrated strong colocalization with the nucleoporin RanBP2. In vitro studies revealed that lipotoxic (palmitic acid) and inflammatory (IL-1β) stimuli induced SHP nuclear translocation, an effect abolished by PKCζ inhibition. SHP knockdown enhanced basal innate immune activation, promoted intracellular lipid accumulation, and reproduced a cholestatic gene-expression pattern characteristic of MASH. Co-immunoprecipitation assays further demonstrated that inflammatory stimulation weakened SHP–LSD1 binding while preserving the interaction between SHP and IκB.
Conclusions: Nuclear accumulation of SHP is a characterized molecular feature of MASH. This PKCζ-dependent translocation appears to function as a compensatory mechanism that mitigates hepatic inflammation and cholestatic stress in the setting of lipotoxic and inflammatory injury.

中文摘要												 		 ii
Abstract											      			 iii
Acknowledgement													 iv
Table of contents													 v
List of Tables											            vii
List of Figures										           viii
Abbreviations													 ix
Chapter 1. Introduction												1
1 Introduction of metabolic dysfunction-associated liver disease (MASLD) 		1
1.1 Diagnostic criteria of MASLD										1
1.2 Metabolic dysfunction-associated steatohepatitis 						1
2 Introduction of bile acids (BAs)										1
2.1 BAs are synthesized from cholesterol, modified by liver and gut microbiota.	2
3 The nuclear receptor SHP act as a central regulator of BA homeostasis 		2
3.1 SHP exerted anti-inflammatory characters in animal and in-vitro model	3
3.2 Contradictory data regard the role of SHP in the pathogenesis of MASH 	3
4 Mechanism of nuclear translocation of SHP 								4
4.1 PKCζ plays a role in the pathogenesis of MASH							4
4.2 RanBP2 is a SUMO-ligase that controls nuclear translocation of SHP 		5 
5 Study design and perspectives											5
Chapter 2. Materials and methods										6
1 Clinical cohort study 												6
1.1 Inclusion and Exclusion Criteria for MASH Patients and Controls 			6
1.2 Examination of pathological characteristics 							6
1.3 Hepatic lipid quantification 											7
1.4 Analysis of serum and fecal BA profile 								7
1.5 Analysis of mRNA 												7
1.6 Immunofluorescent staining											7
1.7 Tissue staining quantification 										8
2 In vitro study 														8
2.1 Cell culture and treatment											8
2.2 Extraction and purification of plasmids									8
2.3 Knockdown of SHP												8
2.4 Overexpression of SHP												9
2.5 Cell staining and quantification										9
2.6 Immunoblotting													9
2.7 Co-immunoprecipitate										   	10
2.8 Statistical analysis												10
Chapter 3. Results													11
1 Clinical study results												11
1.1 MASH patients exhibit increased body weight, metabolic dysregulation, and hepatic injury 													11
1.2 MASH patients had significantly increased serum primary BAs			11
1.3 MASH patients had significantly increased fecal secondary BAs			12
1.4 Hepatic BA transcriptomes in MASH demonstrate a cholestatic trend		12
1.5 MASH patients showed increased hepatocellular nuclear FXR			13
1.6 MASH patients exhibited elevated hepatocellular nuclear SHP			13
1.7 Increased hepatocellular nuclear SHP did not suppress BA synthesis		13
1.8 Increased nuclear SHP was associated with hepatic steatosis and inflammatory activity															14
1.9 Elevated nuclear SHP correlated with key clinical characteristics related to MASH															14
1.10 Hepatic PKCζ was activated, and RanBP2 showed strong colocalization with nuclear SHP in MASH												15
2 In vitro study results 											15
2.1 SHP nuclear translocation induced by lipotoxic and inflammatory stimuli is dependent on PKCζ activation										15 
2.2 SHP silencing enhanced innate immune mediators and stimulates a cholestatic gene signature, whereas overexpressing SHP attenuates the inflammation		16
2.3 SHP knockdown promoted lipid accumulation and upregulates genes related to de novo lipogenesis													18
2.4 Under inflammatory stimulation, SHP reduced its interaction with BA related proteins, while maintained it interaction with inflammatory mediator			18
Chapter 4. Discussion												20
1 Enhanced hepatocellular nuclear SHP was a pathological hallmark in MASH patients	20
1.1 Increased nuclear SHP did not correspond to suppression of BAs		20
1.2 Novelty of enhanced hepatocellular nuclear SHP in MASH				20
2 SHP exerted anti-inflammatory effect 								21
2.1 SHP suppressed NF-κB related signaling axis						21
2.2 SHP suppressed innate immunity through interacting with NLRP3 inflammasome														21
2.3 Reduced hepatic mRNA of SHP point out an autoregulatory mechanism in MASH															21
3 PKCζ and RanBP2 were key proteins critical for nuclear translocation of SHP 22
3.1 Activation of PKCζ was pivotal for the nuclear translocation SHP in MASH 																	22
3.2 RanBP2 was involved in nuclear translocation of SHP in MASH		23
4 Complexity of BA dysregulation in MASH							23
4.1 Elevated serum BAs suggested impaired suppressive function of SHP in MASH 
23
4.2 Distinctive components of serum and fecal BAs in human MASH		23
4.3 Elevated PEPCK might be an adaptive response to mitigate hepatic steatosis 																	24
5 Study limitations 												24
5.1 Limited evidence of direct protein-protein interaction in the presenting study																	24
5.2 Potential influence of medications on IL-1β signaling could not be excluded.																	25

Chapter 5. Conclusions												26
References														27
Tables															32
Figures															39
                                    

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