上海肝病在线 Shanghai Liver Diseases' Online

从实验结果谈北方人的“大块吃肉，大碗喝酒”的科学道理

本版主因工作需要，最近在研究国内外脂肪肝的治疗研究文章（国内1千多篇国外2千多篇）时，发现美国几篇研究文献的研究结果与我国北方人的“大块吃肉，大碗喝酒”相一致。此类结果表明， 酒精中毒性肝病治疗饮食上，富含饱和脂肪酸的油脂---牛羊（动物）脂、猪油、palm oil 、medium-chain triglycerides 等有保肝作用，而富含多不饱和脂肪酸的油脂--corn oil、fish oil等 则有损肝作用。

研究一：该研究采用酒精中毒性肝损伤大鼠为模型，先采用鱼油+酒精6周造模酒精中毒性肝损伤模型----脂肪肝、炎症浸润和坏死，再采用鱼油（多不饱和，n-3）或棕榈油（饱和）治疗2周，发现鱼油治疗组没有改善肝脏病损作用，而棕榈油治疗组肝脏基本恢复正常。说明饱和脂肪（脂肪酸）有治疗作用。

Gastroenterology 1995 Aug;109(2):547-54

Comment in: Gastroenterology. 1995 Aug;109(2):617-20

Dietary saturated fatty acids: a novel treatment for alcoholic liver disease.

Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.

Department of Pathology, New England Deaconess Hospital, Boston, Massachusetts, USA.

BACKGROUND & AIMS: Lipid peroxidation may be important in the pathogenesis of alcoholic liver injury. The purpose of this study was to determine whether a saturated fatty acid-based therapy (palm oil) could decrease lipid peroxidation and alcoholic liver injury during ethanol withdrawal.

METHODS: Three groups of male Wistar rats (5 rats/group) were studied. Rats in group 1 were fed a fish oil-ethanol diet for 6 weeks; rats in groups 2 and 3 were fed a fish oil-ethanol diet for 6 weeks before treatment with fish oil-dextrose (group 2) or palm oil-dextrose (group 3) for 2 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, fatty acid composition, cytochrome P450 2E1 activity, and tocopherol levels.

RESULTS: By 6 weeks, all rats had developed fatty liver, inflammation, and necrosis. Group 2 showed minimal histological improvement, whereas group 3 showed near normalization of the histology. The improvement in group 3 was associated with decreased lipid peroxidation and P450 2E1 activity. Higher levels of omega-3 fatty acids were detected in group 2 than group 3. Tocopherol levels were similar among the groups.

CONCLUSIONS: A diet enriched in saturated but not unsaturated fatty acids reversed alcoholic liver injury. This effect may be explained by down-regulation of lipid peroxidation.

PMID: 7615205

研究二/三/四.....：本版主研究有关不同油脂对酒精性肝损伤的作用研究发现，不同油脂的保肝作用与其饱和脂肪酸含量有关，而加重肝损作用与其不饱和作用有关，因此对于酒精性肝损伤上，保肝上牛羊（动物）脂（只保肝，不损肝）》猪油（保肝明显，不显肝损）》palm oil ，medium-chain triglycerides（保肝不显肝损）》corn oil（损肝而不益肝）》fish oil （严重损肝）。中医要病人少吃鱼（海鱼的油不是好油，但对心血管与肾病则鱼油是好油）有道于酒精性肝病治疗中，但少吃肉如牛羊猪肉则可能道理底气不足啊？？

J Pharmacol Exp Ther 2001 Nov;299(2):638-44

Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration.

Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.

Department of Pathology and Center for the Study of Liver Diseases, The University of Hong Kong, Hong Kong, China. ananji@pathology.hku.hk

We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-kappaB (NF-kappaB) activation, and mRNAs for cyclooxygenase-2 (Cox-2) and tumor necrosis factor-alpha (TNF-alpha). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-kappaB, and mRNAs for Cox-2 and TNF-alpha. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-kappaB activation, and reduced expression of TNF-alpha and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-kappaB and reduced levels of TNF-alpha and Cox-2.

PMID: 11602676

Alcohol Clin Exp Res 1991 Dec;15(6):1060-6

Effect of dietary fat on Ito cell activation by chronic ethanol intake: a long-term serial morphometric study on alcohol-fed and control rats.

Takahashi H, Wong K, Jui L, Nanji AA, Mendenhall CS, French SW.

Department of Internal Medicine, National Kurihama Hospital, National Institute on Alcoholism of Japan, Kanagawa.

We studied the effects of long-term ethanol ingestion and dietary fat on Ito cell activation morphometrically in rats. Sixteen pairs of Wistar male rats were divided into two groups, one fed tallow and the other fed corn oil as the source of dietary fat. Each group of rats were pair-fed a nutritional adequate liquid diet containing either corn oil (CF) or tallow (TF) as fat as well as protein and carbohydrate. Half of each group received ethanol, the rest were pair-fed isocaloric amounts of dextrose via an implanted gastric tube for up to 5 months. Morphometric analysis of the change in fat and rough endoplasmic reticulum (RER) of Ito cells was performed on electron micrographs obtained from monthly biopsies including baseline. Ito cell activation was assessed by a decrease in the ratio of fat/RER in Ito cells. The ratio of fat/RER in Ito cells of alcoholic rats fed the CF diet (CFA) gradually decreased. The ratio was found to be lower than in the pair-fed control rats (CFC) at 5 months of feeding. CFA: 1.74 +/- 0.57, vs. 7.46 +/- 2.05, respectively, p less than 0.05, mean +/- SE). Ito cell fat also significantly decreased at 5 months of feeding (p less than 0.05). The fat/RER ratio in CFA significantly decreased only subsequent to the development of fatty change, necrosis, and inflammation followed by fibrosis of the liver. In contrast, the TFA rats did not show a significant decrease in the fat/RER ratio in the Ito cells throughout the study, while TFC rats showed an increase in the fat/RER ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 1789382

Alcohol Clin Exp Res 1994 Aug;18(4):902-8

Changes in cytochromes P-450, 2E1, 2B1, and 4A, and phospholipases A and C in the intragastric feeding rat model for alcoholic liver disease: relationship to dietary fats and pathologic liver injury.

Nanji AA, Zhao S, Lamb RG, Dannenberg AJ, Sadrzadeh SM, Waxman DJ.

Department of Pathology, New England Deaconess Hospital.

The influence of dietary fat and alcohol on hepatic microsomal levels of cytochromes P-450 2E1, 2B, and 4A; phospholipases A and C; and UDP-glucuronosyltransferase was studied in the intragastric feeding rat model for alcoholic liver injury. Eight groups of animals were evaluated. Control and ethanol fed rats received either saturated fat or corn oil and were killed after 2 weeks and 1 month of feeding. All animals were pair-fed by continuous infusion of liquid diet through permanently implanted gastric cannulas. Alcoholic liver injury developed only in the corn oil-ethanol-fed groups and was manifest by 1 month. Livers were subjected to the following analyses: pathologic evaluation of liver injury; levels of cytochromes P-450 2E1, 2B, and 4A protein and mRNA; aniline hydroxylase activity; and phospholipase A and C and UDP-glucuronosyltransferase activities. Ethanol-induced increases in cytochromes P-450 2E1 and 2B protein determined by Western blotting were greatest in the corn oil-ethanol-fed group, which developed pathologic changes in the liver. Cytochromes P-450 2E1 and 2B1 mRNA levels were unaffected, suggesting that posttranscriptional mechanisms are responsible for the increase in the corresponding P-450 proteins. In contrast, cytochrome P-450 4A levels were higher in the saturated fat-ethanol groups compared with the corn oil-ethanol groups. Phospholipase A and phospholipase C levels were higher in the corn oil-ethanol groups compared with pair-fed dextrose controls and the saturated fat-ethanol groups. UDP-glucuronosyltransferase levels declined with time in the ethanol-fed groups.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 7978103

Alcohol Clin Exp Res 1989 Feb;13(1):15-9

Comment in: Alcohol Clin Exp Res. 1990 Aug;14(4):632.

Beef fat prevents alcoholic liver disease in the rat.

Nanji AA, Mendenhall CL, French SW.

Department of Pathology, University of Ottawa, Canada.

The amount and type of dietary fat is thought to be important in the pathogenesis of alcoholic liver disease (ALD). We investigated the role of different dietary fats in our rat model for ALD. Liver pathology was evaluated in rats fed ethanol and lard or tallow or corn oil over a period of 2 to 6 months. All experimental animals were pair-fed the same diet as controls except that glucose was isocalorically replaced by ethanol. Rats fed tallow and ethanol developed none of the features of ALD, those fed lard and ethanol developed minimal to moderate disease, rats fed corn oil and ethanol developed the most severe pathology. The degree of histopathological abnormality correlated with the linoleic acid content of fat in the diet (tallow 0.7%, lard 2.5%, corn oil 56.6%). We postulate that linoleic acid facilitates development of ALD and provides an explanation for our previous epidemiological observations.

PMID: 2646971

Hepatology 1998 May;27(5):1317-23

Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil.

Polavarapu R, Spitz DR, Sim JE, Follansbee MH, Oberley LW, Rahemtulla A, Nanji AA.

Department of Pharmacology, Pennsylvania State University, Hershey, USA.

Increased hepatic oxidative stress with ethanol administration is hypothesized to be caused either by enhanced pro-oxidant production or decreased levels of antioxidants or both. We used the intragastric feeding rat model to assess the relationship between hepatic antioxidant enzymes and pathological liver injury in animals fed different dietary fats. Male Wistar rats (5 per group) were fed ethanol with either medium-chain triglycerides (MCTE), palm oil (PE), corn oil (CE), or fish oil (FE). Control animals were fed isocaloric amounts of dextrose instead of ethanol with the same diets. The following were evaluated in each group: liver pathology, lipid peroxidation, manganese superoxide dismutase (MnSOD) levels, copper-zinc SOD (CuZnSOD) levels, glutathione peroxidase (GPX) levels, and catalase (CAT) levels. All enzymes were evaluated using activity assays and immunoblots. Rats fed FE showed the most severe pathology (fatty liver, necrosis, and inflammation), those fed CE showed moderate changes, those fed PE showed fatty liver only, and those fed MCTE were normal. Parameters indicative of lipid peroxidation (conjugated dienes and thiobarbituric acid-reactive substances) were also greater in rat livers from animals fed the diets high in polyunsaturated fatty acids (CE and FE). CuZnSOD, GPX, and CAT activities showed an inverse correlation (r=-.92, P < .01) with severity of pathological injury, with the lowest levels for both enzymes found in FE-fed rats. Decreased enzyme activity in CE- and FE-fed rats was accompanied by similar decreases in immunoreactive protein. Ethanol administration did not cause significant decreases in enzyme activity in groups that showed no necroinflammatory changes (MCTE and PE). MnSOD activity showed no significant change in any ethanol-fed group. Our results show that decreases in CuZnSOD, GPX, and CAT occur in rats showing pathological liver injury and also having the highest levels of lipid peroxidation. These results suggest that feeding dietary substrates that enhance lipid peroxidation can exacerbate both ethanol-induced oxidative damage as well as necroinflammatory changes. The decrease in activity of antioxidant enzymes observed in animals fed diets high in polyunsaturated fatty acids and ethanol could possibly increase the susceptibility to oxidative damage and further contribute to ethanol-induced liver injury.

PMID: 9581686

Hepatology 1997 Dec;26(6):1538-45

Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat.

Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

We investigated the potential of dietary saturated fatty acids to decrease endotoxemia and suppress expression of cyclooxygenase 2 (Cox-2) and tumor necrosis factor alpha (TNF-alpha) in established alcohol-induced liver injury. Six groups (five rats/group) of male Wistar rats were studied. Rats in group 1 were fed a fish oil-ethanol diet for 6 weeks. Rats in groups 2, 3, and 4 were fed fish oil and ethanol for 6 weeks. Ethanol administration was stopped at this time, and the rats were switched to isocaloric diets containing dextrose with fish oil (group 2), palm oil (group 3), or medium-chain triglycerides (group 4) as the source of fat for an additional 2 weeks. Rats in groups 5 and 6 were fed fish oil-ethanol and fish oil-dextrose, respectively, for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, and levels of messenger RNA (mRNA) for Cox-2 and TNF-alpha. Concentrations of endotoxin were determined in plasma. The most severe inflammation and fibrosis were detected in groups 1 and 5, as were the highest levels of endotoxin, lipid peroxidation, and mRNA for Cox-2 and TNF-alpha. After ethanol was discontinued, there was minimal histological improvement in group 2 but near normalization of the histology, including regression of fibrosis, in groups 3 and 4. Histological improvement was associated with decreased levels of endotoxin, lipid peroxidation, and reduced expression of Cox-2 and TNF-alpha. The data indicate that a diet enriched in saturated fatty acids (groups 3 and 4) effectively reverses alcohol-induced liver injury, including fibrosis. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased levels of TNF-alpha and Cox-2.

PMID: 9397995

J Lipid Res 1995 Apr;36(4):736-44

Effect of type of dietary fat and ethanol on antioxidant enzyme mRNA induction in rat liver.

Nanji AA, Griniuviene B, Sadrzadeh SM, Levitsky S, McCully JD.

Department of Pathology, New England Deaconess Hospital, Boston, MA, USA.

We carried out a study to relate the effect of the type of dietary fat and ethanol on antioxidant enzyme mRNA levels in liver in the intragastric feeding rat model. Different types of dietary fat were administered [saturated fat (SE), corn oil (CE) and fish oil (FE)] with ethanol to induce varying severities of liver injury. Ethanol-fed rats were pair-fed with dextrose-fed controls that received isocaloric amounts of dextrose. All animals were killed at 1 month and the following studies were carried out: evaluation of severity of pathologic liver injury, mRNA quantitation for catalase, glutathione peroxidase (GPx), and manganese superoxide dismutase (MnSOD), microsomal conjugated dienes, and hydrogen peroxide. SE animals had no liver injury, FE animals had severe liver injury, and CE animals had moderate liver injury. Ethanol induced GPx mRNA in all dietary groups, with the highest levels seen in the FE group. The pattern of catalase mRNA induction was similar to that of GPx mRNA. In contrast, MnSOD mRNA was decreased compared to controls in animals that developed pathologic liver injury, i.e., CE and FE groups. A positive correlation was seen between conjugated diene levels and GPx mRNA (r = 0.88, P < 0.01) and catalase mRNA. The similar slopes for the relationship between conjugated dienes and catalase in the fish oil and non-fish oil groups indicate that the same degree of lipid peroxidation increases catalase mRNA to a greater degree in fish oil-fed rats. A positive correlation was also seen between catalase mRNA and H2O2 (r = 0.95, P < 0.001).

PMID: 7616120