氧化苦参碱在db/db小鼠非酒精性脂肪性肝病中的抗炎机制

目的通过观察db/db小鼠非酒精性脂肪性肝病(NAFLD)中骨成形蛋白-激活素膜结合阻断因子(BAMBI)、NLRP3炎症小体的表达情况及氧化苦参碱(OMT)治疗后的变化,初步探讨OMT改善db/db小鼠NAFLD炎症反应的可能机制。方法db/db小鼠随机分成模型组和OMT给药组,OMT组给予60 mg/(kg·d)OMT腹腔注射,同期wt/wt小鼠为正常对照组,每组6只。油红O染色、HE染色和组织上清液ALT、AST检测评估NAFLD模型一般情况;免疫组化观察肝组织中BAMBI、NLRP3蛋白表达,qPCR观察肝组织中BAMBI、NLRP3 mRNA表达水平;Western blot观察肝组织中BAMBI、NLRP3炎症小体相关指标、Ⅳ型胶原(COLⅣ)、纤维连接蛋白(FN)蛋白水平变化;spearman秩相关分析对BAMBI和NLRP3进行相关性分析。结果 NAFLD模型组HE染色、油红O染色及ALT、AST检测提示存在肝细胞损伤且肝脏有脂质积累。NAFLD模型组相比正常对照组,BAMBI表达量降低,NLRP3表达量增多,COLⅣ、FN表达量增多,OMT治疗后降低了肝脏脂质积累,小鼠肝组织中BAMBI表达量有增加,炎症及纤维化指标均有改善。统计学分析结果提示BAMBI和NLRP3呈显著负相关(P0.05)。结论 OMT可促进NAFLD肝组织中BAMBI表达水平增多,抑制炎症及纤维化反应,提示OMT可能通过影响BAMBI抑制db/db NAFLD小鼠的炎症及纤维化进程。     

异丙肾上腺素下调NADPH氧化酶负调控瘦素表达加剧db/db小鼠心功能异常

目的:分析异丙肾上腺素加剧db/db小鼠心功能损伤的瘦素参与机制及NADPH氧化酶的调控作用。方法:18只野生型小鼠和18只db/db小鼠分别随机分为3组:对照组、异丙肾上腺素组和NADPH氧化酶apocynin组(n均=6)。除对照组外,其余两组小鼠给予异丙肾上腺素皮下注射(1mg/kg),连续6天,apocynin组小鼠第4天起给予apocynin(100mg/kg)灌胃治疗。分析各组小鼠心脏指数,并检测心肌组织中NADPH氧化酶亚基、瘦素及基质金属蛋白酶(MMP)和抑制剂表达。结果:与对照组比较,异丙肾上腺素组小鼠心功能明显异常(P0.01),且NADPH氧化酶亚基p22phox、p47phox、p67phox、gp91phox及瘦素表达明显升高(P0.01),MMP2/9和TIMP1/2也明显升高(P0.01),而apocynin组小鼠上述指标异常得到明显改善(P0.01)。结论:异丙肾上腺素通过下调NADPH氧化酶负调控瘦素表达加剧db/db小鼠心肌功能异常。     

2型糖尿病模型db/db小鼠海马NOS阳性神经元变化

目的　观察人类 2型糖尿病模型———C5 7BL/KsJdb/db(db/db)小鼠海马NOS阳性神经元变化。方法　糖尿病组 :6周龄C5 7BL/KsJ(db +db +)小鼠 5只 ,尾静脉空腹血糖高于 11.1mmol/L且肥胖。对照组 :非糖尿病小鼠C5 7BL/KsJ(?+) 5只 ,尾静脉空腹血糖低于 6 .0mmol/L体重正常 ,于 30周龄 (成模第 6月末 )时 ,灌注固定取脑 ,以NADPH d组化法显示海马NOS阳性神经元。结果　与正常对照组相比 ,糖尿病组小鼠海马齿状回NOS阳性神经元密度显著减少 (P <0 0 1)。结论　糖尿病时NOS阳性神经元数量减少 ,NO的合成降低表明NO可能参与糖尿病中枢神经系统功能障碍     

阿托伐他汀诱导Nrf2缓解非酒精性脂肪性肝病大鼠肝变性

目的 观察阿托伐他汀对非酒精性脂肪性肝病(NAFLD)大鼠肝的保护作用,并探讨其作用机制。方法 取50只健康SD大鼠,随机分为对照组、模型组、阿托伐他汀低剂量组、阿托伐他汀中剂量组、阿托伐他汀高剂量组,每组10只。除对照组采用普通饲料喂养外,其余各组均采用高脂饲料喂养诱导NAFLD模型;阿托伐他汀低剂量组、阿托伐他汀中剂量组、阿托伐他汀高剂量组每日灌胃2.5 mg/kg、5.0 mg/kg、10.0 mg/kg阿托伐他汀,连续4周。实验结束后,检测血清天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血糖及血清胰岛素水平;检测肝组织丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)水平;通过HE染色观察大鼠肝组织病理改变;TUNEL染色检测肝细胞凋亡情况;Western blot检测肝组织核因子相关因子2(Nrf2)、p-Nrf-2、血红素加氧酶(HO-1)和奎宁氧化还原酶1(NQO1)表达。结果 阿托伐他汀能明显减轻高脂诱导的NFALD大鼠的体质量增加、胰岛素抵抗、血脂异常...     

小热休克蛋白家族和自噬相关蛋白 在自发性2型糖尿病db/db小鼠海马组织中的表达

目的观察自发性2型糖尿病db/db小鼠海马组织中小热休克蛋白家族(sHSPs)及自噬相关蛋白表达情况。方法正常db/m小鼠作为对照组,糖尿病db/db小鼠作为模型组,各10只。观察其体质量,空腹血糖(FBG);real-time PCR检测海马组织中小热休克蛋白家族、自噬相关基因mRNA的表达;Western blot检测HSPB8、BAG3、LC3、P62蛋白表达。结果 1)db/db小鼠体质量、空腹血糖均明显高于db/m小鼠(P0.01)。2)小热休克蛋白1-10(heat shock protein family B [small] member 1-10,HSPB 1-10)基因mRNA在小鼠海马组织中均有表达;其中HSPB1、HSPB3、HSPB5、HSPB6和HSPB8 db/db组明显低于db/m组(P0.05);HSPB2、HSPB9和HSPB10 db/db组高于db/m组(P0.05);而在db/db小鼠中LC3表达高于db/m组(P0.01),而P62反之(P0.01)。3)较db/m组,db/db组HSPB8、BAG3、LC3-Ⅱ蛋白表达均增高(P0.01),相反P62蛋白表达减低(P0.05)。结论 1)10种sHSPs均在小鼠海马组织中表达,但表达特点有所不同。2)8周龄糖尿病小鼠海马组织中存在HSPB8蛋白表达增强,且自噬激活。     

抑制髓样细胞触发受体-1(TREM-1)减轻慢性间歇性低氧诱发的模型小鼠动脉粥样硬化

目的 探究髓样细胞触发受体-1(TREM-1)在慢性间歇性低氧(CIH)诱发的动脉粥样硬化(AS)中作用。方法 将ApoE^-/-小鼠随机分为空白组、模型组和实验组。模型组和实验组小鼠饲养于低氧环境,给予高脂饲料喂养;实验组小鼠高脂饲养4周后,腹腔注射TREM-1抑制剂LR12(5 mg/kg),连续干预8周。饲养12周后,检测血清总胆固醇(TC)、低密度脂蛋白(LDL)、三酰甘油(TG)、肿瘤坏死因子α(TNF-α)、白细胞介素1(IL-1β)、白细胞介素10(IL-10)水平;组织学分析主动脉TREM-1表达、斑块面积及巨噬细胞水平。结果 与空白组相比,模型组小鼠主动脉TREM-1表达量显著升高(P<0.05)。相比于模型组,实验组小鼠主动脉斑块显著减少,血清血脂(TC、LDL、TG)及炎性因子(TNF-α、IL-1β、IL-10)水平显著降低,主动脉斑块及斑块浸润巨噬细胞、TREM-1表达显著减少(P<0.05),且斑块中TREM-1表达与巨噬细胞为共定位。结论 TREM-1参与CIH诱发的AS发生发展,抑制TREM-1能够减轻CIH诱发的AS,其...     

甜菊糖甙对db/db小鼠胰岛素抵抗和胰岛炎症的影响

目的：大量证据显示,胰岛的炎症反应和胰岛素抵抗是db/db小鼠发生2型糖尿病（DM2）的两个主要因素。甜菊糖甙是一种从菊科植物中提取的天然化合物对于糖尿病病人有许多益处。本实验试图观察甜菊糖甙是否能够改善db/db小鼠的胰岛素抵抗和胰岛炎症反应,从而改善糖代谢。方法：给予db/db小鼠甜菊糖甙或者空白溶剂处理2个月。在处理结束时观察空腹血糖和胰岛素耐量,同时分离胰岛行葡萄糖刺激的胰岛素分泌试验,并行胰腺组织免疫荧光观察胰岛内巨噬细胞浸润情况。结果：甜菊糖甙干预2个月不影响db/db小鼠体重,但显著降低小鼠的空腹血糖,明显改善胰岛素抵抗。同时葡萄糖刺激的胰岛素分泌试验结果提示,甜菊糖甙可显著提高db/db小鼠胰岛在体外分泌胰岛素的能力。此外,免疫荧光提示,甜菊糖甙能显著减轻db/db小鼠胰岛内巨噬细胞浸润程度明显减轻和改善胰岛炎症反应。结论：甜菊糖甙能通过改善胰岛素抵抗和胰岛炎症反应来改善db/db小鼠的糖代谢和胰岛素分泌能力。     

阿托伐他汀钙对非酒精性脂肪肝脂质储积的影响

目的探讨阿托伐他汀钙对非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的肝脏脂质储积的影响。方法利用不同程度的高脂饮食建立正常体重和超重的小鼠NAFLD模型,阿托伐他汀每天20 mg/kg灌胃10天,HE染色观察肝脏组织学形态,脂质定量试剂盒检测肝脏脂质含量,血生化检测小鼠肝脏功能变化。收集临床数据,回顾性分析101例NAFLD患者,按体重指数分为正常体重(18.5≤BMI24,n=48)和超重组(BMI≥24,n=53),分别检测阿托伐他汀钙治疗前后患者肝功能、血浆脂肪指标,并通过肝脏常规超声检查评估脂肪肝严重程度的变化。结果 35%高脂饮食的小鼠体重和正常饮食的小鼠体重相比,差异无显著性;58%高脂饮食小鼠体重较正常饮食小鼠体重显著增加。阿托伐他汀每天20 mg/kg灌胃10天后,HE染色显示58%高脂饮食小鼠脂肪肝程度较35%高脂饮食小鼠减轻更为显著。肝脏脂肪含量检测显示35%高脂饮食小鼠及58%高脂饮食小鼠肝脏总胆固醇(total cholesterol,TC)和甘油三酯(triglyceride,TG)含量均较前下降,且58%高脂饮食小鼠比35%高脂饮食小鼠下降更为明显。临床治疗数据分析显示,患者每天服用20 mg阿托伐他汀钙治疗6个月后,正常体重组和超重组患者血浆TC、TG均较治疗前有不同程度的下降,且超重组血中TC和TG下降较正常组更为明显。肝脏常规超声结果也显示阿托伐他汀钙能够明显降低患者肝脂肪变程度,且超重组患者受益更为明显。结论阿托伐他汀钙可用于NAFLD的治疗,且对超重患者脂肪肝的改善效果更为明显。     

余甘子提取物对幼鼠非酒精性脂肪肝病的防治作用

目的探讨余甘子提取物对高脂饮食诱导幼鼠非酒精性脂肪肝病的防治作用。方法 48只3周龄SD大鼠随机分为对照组、造模组、二甲双胍组和余甘子提取物低、中、高剂量组。对照组进食普通饲料,其余组进食高脂饲料,每日定时灌胃:二甲双胍组予二甲双胍混悬液250 mg/kg,低、中、高剂量组分别予余甘子提取物250、500和1 000 mg/kg,对照组、造模组予等量生理盐水,饲养及给药6周。检测:①体质量、肝重,计算肝指数;②测血清AST、ALT、TG、LDL、GLU、CHO、INS含量,计算HOMA-IR指数;③HE染色观察肝组织病理形态,进行NAS评分。结果造模组体质量、肝重、ALT、AST、CHO高于对照组,中、高剂量组体质量低于造模组,差异有统计学意义(P0.05)。低剂量组ALT、AST、CHO低于造模组(P0.05),中剂量组ALT、AST、CHO、LDL低于造模组(P0.05),高剂量组ALT、AST、CHO低于造模组(P0.01)。各剂量组NAS分值较造模组下降(P0.05),肝细胞脂肪变有改善。结论余甘子提取物可减轻高脂饲料诱导的幼鼠肝脂肪变病变程度,改善肝功能,起到防治作用。     

SPARC在db/db小鼠肾脏组织中高表达

目的 检测db/db鼠肾脏组织中的富含半胱氨酸的酸性分泌蛋白(SPARC)的表达情况.方法 RT-PCR、Western blot及免疫荧光方法检测db/db鼠肾脏组织中的SPARC mRNA及蛋白的表达.结果 SPARC在db/db鼠肾脏组织中呈现高表达.结论 db/db鼠肾脏组织中的SPARC呈现高表达(P＜0.05),可能与糖尿病肾病的发生与发展有关.     

Impaired liver regeneration after partial hepatectomy in db/db mice

Fatty liver is the most common hepatic disorder in humans and supposed to be a cause of poor prognosis after liver transplantation and hepatic resection which could be resulted from impaired liver regeneration. This study was carried out to analyze the process of liver regeneration in db/db mice which show severe steatosis because of abnormal leptin receptor. We performed 70% partial hepatectomy (PH) on db/db mice and normal +m/+m mice, and then sacrificed the animals 1, 2, 3, 5, 7 and 10 days later. The liver samples were weighed and examined histologically or immunohistochemically. As a result, the liver mass restitution was significantly inhibited in db/db mice compared with +m/+m mice. The BrdU labelling index peaked at 2 days after PH in both strains, although the value was lower in db/db mice. After that, interestingly, it decreased to the control level at 5 days in +m/+m mice while the recovery was delayed in db/db mice. Similar sequence was also observed in the PCNA labelling index. In addition, the peak time of the mitosis index was 2 days and 5 days after PH in +m/+m mice and in db/db mice, respectively. Thus, although not significant, the proliferative response of hepatocytes to PH occurred somewhat more transient and sharply in +m/+m mice while it lasted somewhat longer in db/db mice. This suggests that db/db mice may be valuable as one of the animal models for the investigation of the effects of steatosis on the liver regeneration.     

Japanese herbal medicines shosaikoto,inchinkoto, and juzentaihoto inhibit high‐fat diet‐induced nonalcoholic steatohepatitis in db/db mice

Few studies have investigated the effects of Japanese herbal medicines on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). To the best of our knowledge, only one study has examined whether high‐fat (HF) diet‐fed db/db mice are appropriate animal models of NASH. We investigated the effects of four types of Japanese herbal medicines (shosaikoto (TJ‐9), inchinkoto (TJ‐135), juzentaihoto (TJ‐48), and keishibukuryogan (TJ‐25)) on hepatic lesions of HF diet‐fed db/db mice. Db/db mice were divided into six groups: control diet (control); HF diet (HF); and HF diet supplemented with TJ‐9, TJ‐135, TJ‐48, or TJ‐25 (TJ‐9, TJ‐135, TJ‐48, and TJ‐25, respectively). Mice were killed after 6 weeks of treatment, and biochemical and pathological analyses were performed. Mice in the HF group consistently developed histopathological features consistent with definite NASH, and marked necroinflammation occurred. Serum alanine aminotransferase levels in the TJ‐9, TJ‐135, and TJ‐48 groups were significantly improved compared with those in the HF group. With regard to liver histology, TJ‐9 and TJ‐48 significantly improved lobular inflammation, and TJ‐135 significantly improved ballooning degeneration. We have shown that HF diet‐fed db/db mice are animal models that correctly recapitulate the histopathology of human NASH and that TJ‐9, TJ‐135, and TJ‐48 inhibit necroinflammatory activity in this model.     

Impaired proliferation of non-parenchymal cells participates in an impairment of liver regeneration in db/db mice

In this study, we examined the possibility that impaired proliferation of non-parenchymal cells affects in an impairment of liver regeneration in db/db mice, which are congenitally deficient in receptors for leptin. Liver regeneration after a two thirds partial hepatectomy (2/3 PH) was impaired in 10-week-old female db/db mice. The proliferation of both hepatocytes and non-parenchymal cells estimated from a bromodeoxyuridine (BrdU) labeling index was suppressed, and the protein expression of vascular endothelial growth factor was blocked in db/db mice. Although the extent of fatty change and the level of epidermal growth factor receptor protein expression in the liver were improved in 5-week-old db/db mice, the regeneration of liver was impaired after 2/3 PH in both 5- and 10-week-old db/db mice. These results suggested that suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration in db/db mice. As leptin has also the angiogenic effect, the angiogenic inhibitor FR-118487 was administered to ICR mice to examine liver regeneration after 2/3 PH, and the rate of regeneration was affected. In conclusion, it is suggested that the suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration probably through a disrupted angiogenesis in db/db mice.     

厄贝沙坦通过诱导自噬减轻db/db小鼠肝脏脂肪变

目的:探讨厄贝沙坦对db/db小鼠脂肪肝的影响及自噬在这一过程中的作用。方法:雄性db/db小鼠24只随机分为模型组和厄贝沙坦组,另选取12只db/m小鼠作为正常对照组。各组分别干预16周后,观察体重、肝指数、血脂、肝功能以及肝脏病理的变化,检测肝组织PI3K/Akt/m TOR信号通路及自噬相关蛋白Atg-7、beclin-1和LC3B的表达情况,并利用电镜观察肝脏自噬小体的变化。结果:与模型组相比,应用厄贝沙坦干预后,db/db小鼠的体重、肝指数、血脂、丙氨酸转氨酶和天冬氨酸转氨酶与模型组相比显著降低(P0.05),肝脏病理改变明显减轻;肝组织p-PI3K、p-Akt和p-m TOR的表达明显减少,Atg-7、beclin-1和LC3B-Ⅱ的表达明显增加,肝脏自噬小体显著增多(P0.05)。结论:厄贝沙坦可能通过抑制PI3K/Akt/m TOR信号通路,上调自噬相关蛋白Atg-7、beclin-1和LC3B-Ⅱ表达,进而促进肝细胞自噬,减轻db/db小鼠肝脏脂肪变。     

Expression of epidermal growth factor receptor protein in the liver of db/db mice after partial hepatectomy

Liver regeneration was impaired after partial hepatectomy (PH) in leptin receptor-deficient db/db mice with severe liver steatosis. In the present study, we analyzed the mode of epidermal growth factor receptor (EGFR) protein expression in the liver of 5- and 10-week-old db/db and age-matched control mice. In 5-week-old db/db mice, neither the expression of EGFR protein in the intact liver nor the rate of liver regeneration after PH was significantly different from that in age-matched control mice. However, in 10-week-old db/db mice, the level of EGFR protein expression was very low and liver regeneration was prominently suppressed. Histopathologically, much severer fatty change was observed in the liver of 10-week-old db/db mice than 5-week-old db/db mice. These results suggest that the down-regulation of EGFR protein expression is associated with an impairment of liver regeneration in db/db mice and that the severity of hepatic steatosis plays an indirect role in the impairment of liver regeneration by modifying EGFR expression.     

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-fed db/db mice

Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3(-/-) or GP130(-/-) mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD diet-fed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.     

非酒精性脂肪肝患者脂代谢紊乱与血清补体C3的相关性研究

目的:研究血清补体C3与非酒精性脂肪肝发病危险因素及非酒精性脂肪肝发生发展的相关性.进而了解C3在非酒精性脂肪肝患者血清中含量变化的意义.方法:40例健康对照组、40例单纯转氨酶升高组、40例非酒精性脂肪肝转氨酶正常组、40例非酒精性脂肪肝转氨酶升高组.按脂肪肝患者ALT是否升高分为转氨酶正常组和异常组.用酶联免疫吸附...     

甘草酸二铵脂质配位体对非酒精性脂肪肝大鼠的治疗作用

Objective To study therapeutic effects and underlying mechanisms of diammonium glycyrrhizinate lipid ligand (DGLL) on nonalcoholic fatty liver disease (NAFLD). Methods Sixty SD rats were randomly divided into six groups(10 rats per group): the model group, 3 DGLL-treated (30, 60, 120mg/kg) groups, the positive control ［treated with biphenyldicarboxylate (200mg/kg)］ group and normal control group. The stomach of the rat of the model group was irrigated with high lipid emulsion. The rats of DGLL groups were irrigated with relative dose of DGLL. After nine weeks, the changes of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL) in serum and the contents of malondialdehyde (MDA), superoxide dismutase (SOD) in liver homogenate were measured; the NF-κB p65 level in liver tissues was observed by immunohistochemistry, respectively. The expressions of NF-κB p65 and I-κBα in liver were determined by Western blotting. BR>Results Compared with the model group, the levels of TC,TG,LDL,MDA were decreased, meanwhile the activity of HDL and SOD were enhanced, the level of NF-κB in liver tissues was ameliorated remarkably by administration of DGLL. Meanwhile, th     

Pathology of the liver in obese and diabetic ob/ob and db/db mice fed a standard or high-calorie diet

Non‐alcoholic fatty liver disease (NAFLD) is one of the commonest liver diseases in Western countries. Although leptin deficient ob/ob and db/db mice are frequently used as murine models of NAFLD, an exhaustive characterization of their hepatic lesions has not been reported to date, particularly under calorie overconsumption. Thus, liver lesions were characterized in 78 ob/ob and db/db mice fed either a standard or high‐calorie (HC) diet, for one or three months. Steatosis, necroinflammation, apoptosis and fibrosis were assessed and the NAFLD activity score (NAS) was calculated. Steatosis was milder in db/db mice compared to ob/ob mice and was more frequently microvesicular. Although necroinflammation was usually mild in both genotypes, it was aggravated in db/db mice after one month of calorie overconsumption. Apoptosis was observed in db/db mice whereas it was only detected in ob/ob mice after HC feeding. Increased apoptosis was frequently associated with microvesicular steatosis. In db/db mice fed the HC diet for three months, fibrosis was aggravated while steatosis, necroinflammation and apoptosis tended to alleviate. This was associated with increased plasma β‐hydroxybutyrate suggesting an adaptive stimulation of hepatic mitochondrial fatty acid oxidation (FAO). Nevertheless, one‐third of these db/db mice had steatohepatitis (NAS ≥ 5), whereas none of the ob/ob mice developed non‐alcoholic steatohepatitis under the same conditions. Steatosis, necroinflammation, apoptosis and fibrosis are modulated by calorie overconsumption in the context of leptin deficiency. Association between apoptosis and microvesicular steatosis in obese mice suggests common mitochondrial abnormalities. Enhanced hepatic FAO in db/db mice is associated with fibrosis aggravation.