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研究生：	廖宣雅 Liao, Hsuan-Ya
論文名稱：	代謝失調性脂肪肝之肝細胞脂滴動態與代謝調控 Dynamics and metabolic regulation of hepatic lipid droplets in metabolic dysfunction-associated fatty liver disease
指導教授：	楊孔嘉 Young, Kung-Chia
學位類別：	碩士 Master
系所名稱：	醫學院 - 醫學檢驗生物技術學系 Department of Medical Laboratory Science and Biotechnology
論文出版年：	2025
畢業學年度：	113
語文別：	英文
論文頁數：	165
中文關鍵詞：	代謝相關脂肪肝病、非酒精性脂肪性肝炎、燃盡型非酒精性脂肪性肝炎、肝臟脂肪變性、脂滴、脂解作用、Brunt評分系統、脂質自噬、含馬鈴薯樣磷脂酶結構域蛋白2 (PNPLA2)
外文關鍵詞：	Metabolic associated fatty liver disease (MAFLD), non-alcoholic steatohepatitis (NASH), burned-out NASH, hepatic steatosis, lipid droplet, lipolysis, Brunt scoring system, lipophagy, Patatin-like phospholipase domain-containing protein 2 (PNPLA2)
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在代謝相關脂肪肝疾病（MAFLD）中，先前研究利用超音波技術發現較嚴重的階段（如纖維化或肝硬化階段）肝臟脂肪可能會下降，然而肝臟脂肪含量及脂滴（LD）動態變化之代謝與致病意義尚未明確。為了探究肝臟脂肪含量與脂滴在MAFLD進程中的動態變化，本研究首先由病理科醫師依照Brunt評分系統 ( Brunt scoring system ) 評估72位MAFLD病人的肝臟切片肝炎嚴重程度，得到所有病人之NASH分級、纖維化等級 ( fibrosis stage ) 及肝脂肪含量。之後再利用光柵掃描法（raster scan method）結合 ImageJ 分析，量化脂滴面積百分比、每個視野的平均脂滴數量，以及平均脂滴直徑。研究同時評估了擴展性肝細胞腫脹（extended hepatocyte ballooning score, eB score）與小葉發炎評分( lobular inflammation score )。接著分析每位病人的小葉性發炎分數( lobular inflammation score )與擴展性肝細胞膨脹分數（eB score），並將病人的病歷資料，組織學判讀結果與脂滴定量結果一併分析。為了模擬早期與晚期 NASH 中脂滴的形態變化，研究使用初級人類肝細胞（PHH），並分別以油酸（OA）或 SOAT 抑制劑 TMP-153處理，以誘導形成大脂滴或小脂滴。隨後利用免疫螢光染色檢測脂滴相關蛋白，並對OA與TMP-153 處理過的PHH 細胞模型及線上NAFLD 臨床數據資料庫進行RNA定序與轉錄體分析，以探討其代謝與致病途徑。結果顯示，肝脂肪含量在NASH 等級 0 到 1 之間顯著增加（p < 0.0001），而在等級 1 到 2 間則下降（p = 0.0044）。脂滴定量分析顯示從等級 0 到 1，平均脂滴直徑增加（p = 0.0021），而脂滴數量下降（p = 0.0139）；從等級 1 到 2+3，脂滴直徑減小（p = 0.0133），而脂滴數量增加（p = 0.0358）。在 NASH 等級 0 中，肝脂肪含量與NAS分數 ( NAFLD Activity Score , NAS score )與纖維化等級呈正相關，與脂滴數量呈負相關；脂滴面積與直徑均與NAS分數呈正相關。在 NASH 等級 1 中，脂滴的增大（非數量變化）推動了脂質累積；而在等級 2 中，脂滴參數與小葉發炎評分呈負相關，顯示脂解作用可能增加。免疫螢光染色結果顯示在OA 處理 4 天的 PHH（OA 4dt PHH）中，PLIN2 的大小（p < 0.0001）與數量（p = 0.0045）均明顯高於 TMP-153 處理 4 天的 PHH。在先前經 OA 處理後再給予 TMP-153 處理的PHH組別中，PLIN2 的大小顯著下降（p < 0.0001），但數量未明顯改變，顯示 PLIN2 可能發生降解。同樣地，PLIN3 在 OA 處理 2 天的 PHH 中也顯著更大（p = 0.0464）且更多（p < 0.0001），而在隨後 TMP-153 處理後大小顯著下降（p < 0.0001）。相比於 DMSO 對照組，OA 處理兩天的組別與TMP-153 處理兩天的組別均出現 PLIN3 數量較高的情形，顯示 PLIN3可能參與早期脂滴生成。此外，作為大脂滴降解關鍵脂解酶的含馬鈴薯樣磷脂酶結構域蛋白2 (Patatin-like phospholipase domain-containing protein 2, PNPLA2) 基因表現量在 NASH 患者與 TMP-153 處理的 PHHs 中均表達上調，可能導致大脂滴被降解，而小脂滴在疾病後期累積的現象。總結來說，脂滴在早期NASH（等級 0–1）中發生增大與融合，而在晚期NASH（等級 1–2）中則可能出現降解現象，這可能與增強的脂解活性有關。這些脂滴形態的動態變化不僅能反映 MAFLD 進展，更可能對其病程具有調控作用。

In metabolic-associated fatty liver disease (MAFLD), previous imaging-based studies have suggested that hepatic lipid content might decrease in advanced stages such as fibrosis or cirrhosis. However, the changes in lipid droplet (LD) dynamics across disease stages, as well as their metabolic and pathological significance, remain unclear. Thus, liver tissue from 72 MAFLD patients was assessed histologically using the Brunt scoring system to determine NASH grade, fibrosis stage, and relative liver fat content. LDs in the same samples were analyzed using raster scan imaging and ImageJ to quantify LD area (%), mean LD count per field, and mean LD diameter. Extended hepatocyte ballooning (eB) and lobular inflammation scores were also evaluated. To model LD morphology in early vs. advanced NASH, primary human hepatocytes (PHHs) were treated with oleic acid (OA) or the SOAT inhibitor TMP-153 to induce large or small LDs, respectively. Immunofluorescence staining assessed LD-associated proteins, and transcriptomic analyses were performed on both PHH models and public NAFLD clinical datasets to explore metabolic and pathogenic pathways. Liver fat content significantly increased from NASH grade 0 to 1 (p < 0.0001) and decreased from grade 1 to 2 (p = 0.0044). LD quantification revealed that from grade 0 to 1, mean LD diameter increased (p = 0.0021), while LD count decreased (p = 0.0139). From grade 1 to 2+3, LD diameter decreased (p = 0.0133), while LD count increased (p = 0.0358). In NASH grade 0, liver fat positively correlated with NAS and fibrosis stage and negatively with LD count. LD area and diameter were both positively correlated with NAS score. In NASH grade 1, LD enlargement (not count) drove fat accumulation, while in grade 2, LD parameters negatively correlated with lobular inflammation, suggesting increased lipolysis. Immunofluorescence staining showed that PLIN2 was significantly larger (p < 0.0001) and more abundant (p = 0.0045) in OA 4dt PHH compared to TMP-153 4dt PHH. PLIN2 size decreased significantly after TMP-153 treatment following OA exposure (p < 0.0001), without a notable change in count, suggesting PLIN2 degradation. PLIN3 was also significantly larger (p = 0.0464) and more abundant (p < 0.0001) in OA 2dt PHH than in TMP-153 2dt PHH, and its size decreased after TMP-153 treatment (p < 0.0001). Both OA 2dt and TMP-153 2dt groups showed increased PLIN3 counts compared to DMSO controls, implying PLIN3 involvement in early LD biogenesis. PNPLA2, a key lipase for large LD degradation, was upregulated in both NASH patients and TMP-153–treated PHHs, possibly driving small LD accumulation in advanced disease. In conclusion, LDs undergo enlargement and fusion in early NASH (grade 0–1) and degradation in advanced NASH (grade 1–2), likely due to enhanced lipolytic activity. These dynamic changes in LD morphology may not only reflect but also regulate MAFLD progression.

中文摘要	I
Abstract	III
Acknowledgment	V
Contents	VI
Figure Contents	XII
Abbreviations	XIV
I.	Introduction	1
Fatty liver disease	1
1	The definition of MAFLD and NAFLD	1
2	Metabolic-dysfunction-associated fatty liver disease (MAFLD)	1
2.1	Introduction of MAFLD	1
2.2	MAFLD progression	2
2.3	Scoring systems of MAFLD	2
2.3.1 Histological features and scoring systems of MAFLD	2
2.3.2	The Brunt scoring system	4
2.3.3	The NAFLD activity score (NAS)	5
3  Cell model of MAFLD	6
3.1	The treatment of PHH with oleic acid (OA)	6
3.2	The treatment of PHH with SOAT inhibitor TMP-153	7
Lipid droplet (LD)	9
1	Overview of LDs	9
2	LD biogenesis	10
2.1	Neutral lipid synthesis	10
2.2	Lipid nucleation	11
2.3	LD budding	11
3	LD growth and fusion	12
3.1	LD growth	12
3.2	LD fusion	12
4	LD degradation	13
4.1	Lipolysis	13
4.2	Lipophagy	13
4.2.1	Macrolipophagy	13
4.2.2	Microlipophagy	14
4.2.3	Chaperone-mediated autophagy (CMA)	14
Alterations in hepatocyte morphology and signaling pathways during MAFLD progression	14
1 Alteration of hepatocyte morphology in MAFLD progression	14
2 Alteration of signaling pathways in hepatocytes in MAFLD progression	15
Current understanding of hepatic lipid change in MAFLD progression	16
1	Hypothesis of MAFLD progression	16
2	Hepatic lipid change in MAFLD progression	17
What we have known	17
Hypotheses	18
Specific aims of the study	18
Experimental design	19
II.	Materials and methods	20
Photography of MAFLD patient sample	20
Quantification of LD area, mean count, diameter in MAFLD patient liver sections using ImageJ	20
Patient demographic data analysis	21
Cell culture and treatment of OA and TMP-153	21
Reagents of PHH treatment	21
Immunofluorescence of PLIN2, PLIN3, p62 expression	22
Statistical analysis	22
III.	Results	23
LD dynamics across different NASH grades	23
1	Liver fat change and LD area across different NASH grades	23
2	LD count and size changes across different NASH grades	24
3	Change of LD morphology in different NASH grades	24
3.1 Liver fat change and LD area correlation in different NASH grades	24
3.2 Liver fat change, LD count, and diameter correlation in different NASH grades	25
3.3 LD area, count and diameter correlation in different NASH grades	25
LD dynamics across different lobular inflammation score	26
1 Liver fat change, LD area, mean count and mean diameter across different lobular inflammation scores	26
2 Change of LD morphology in different lobular inflammation scores	27
2.1 Liver fat change and LD area correlation in different lobular inflammation	27
2.2 Liver fat change, LD count, and diameter correlation in different lobular inflammation scores	28
2.3 LD area, count and diameter correlation in different lobular inflammation scores	28
3 Correlation of liver fat change, LD area, mean count and mean diameter across different lobular inflammation scores in NASH grade 0, 1, and 2	29
LD dynamics across different extended hepatocyte ballooning (eB) scores	29
1 Liver fat change, LD area, mean count and mean diameter across different eB scores	29
2 Change of LD morphology in different eB scores	30
2.1 Liver fat change and LD area correlation in different eB scores	30
2.2 Liver fat change, LD count and diameter correlation in different eB scores	31
2.3 LD area, LD count, and diameter correlation in different eB scores	31
2.4 LD count and diameter correlation in different eB scores	32
LD dynamics across different fibrosis stages	33
1 Fibrosis stages across different NASH grades, lobular inflammation scores, and eB scores	33
2 Liver fat change, LD area, mean count and mean diameter across different fibrosis stages	33
3 Change of LD morphology in different fibrosis stages	34
3.1 Liver fat change and LD area correlation in different fibrosis stages	34
3.2 Liver fat change, LD count and diameter correlation in different fibrosis stages	35
3.3 LD area, LD count, and diameter correlation in different fibrosis stages	35
4 Correlation of liver fat change, LD area, mean count and mean diameter across different fibrosis stages in NASH grade 0, 1, and 2	36
LD dynamics across different NAS scores and groups defined by combined lobular inflammation and eB scores	36
1 LD dynamics in NAS scores	36
2 LD dynamics in combined lobular inflammation and eB scores	37
Correlation analysis of LD dynamics and all histological parameters	38
1 Analysis of all patients	38
2 Analysis of NASH grade 0 patients	39
3 Analysis of NASH grade 1 patients	40
4 Analysis of NASH grade 2 patients	40
5 Analysis of NASH grade 2+3 patients	41
Correlation analysis of patient demographic parameters with LD morphological parameters and histological parameters	41
LD dynamics and surface protein expression in OA, TMP-153 treated PHH	42
Transcriptomic analysis of MAFLD patient datasets, text-mined gene signatures, and OA- or TMP-153-treated PHH	44
1.	RNA-Seq analysis of NAFL and NASH patient data from the GEO2R database	44
2.	RNA-seq analysis of OA and TMP-153 treated PHH	45
Immunofluorescence staining of PNPLA2 inhibition in TMP-153 treated PHH	46
IV.	Discussion	48
Hepatic lipid content and LD dynamics in NASH progression	48
Correlation of patient demographic parameters with LD and histological parameters	48
Conclusion	50

V.	References	51
VI.	Figures	57
Figure 1	57
Figure 2	60
Figure 3	66
Figure 4	68
Figure 5	75
Figure 6	76
Figure 7	79
Figure 8	86
Figure 9	89
Figure 10	95
Figure 11	98
Figure 12	101
Figure 13	104
Figure 14	110
Figure 15	112
Figure 16	121
Figure 17	124
Figure 18	127
VII.	Table	140
Table 1. Descriptive statistics of MAFLD patients	140
VIII.	Supplementary data	142
Figure S1	142
Figure S2	143
Figure S3	144
Figure S4	145
IX.	Appendix	146
Antibodies	146
Reagents	147
Instruments	148
                                    

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