Diseases of Dairy Animals | Non-Infectious Diseases: Fatty Liver

Diseases of Dairy Animals | Non-Infectious Diseases: Fatty Liver

Non-Infectious Diseases: Fatty Liver S S Donkin, Purdue University, West Lafayette, IN, USA ª 2011 Elsevier Ltd. All rights reserved. Introduction Fa...

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Non-Infectious Diseases: Fatty Liver S S Donkin, Purdue University, West Lafayette, IN, USA ª 2011 Elsevier Ltd. All rights reserved.

Introduction Fatty liver, or hepatic steatosis, is a pathological condition that is caused by chemical, nutritional, genetic, and endocrine perturbations. The condition is often termed a metabolic disease of dairy cattle in that the lipid content of liver deviates from the normal levels of <5% triacylglycerol (TG) (or triacylglyceride). During the late 1970s and early 1980s, fatty liver was recognized as part of a condition known as ‘fat cow syndrome’. Clinical reports indicate that fatty liver occurs in high-yielding dairy cows immediately after calving, particularly when cows are overconditioned. The classic studies of Reid and coworkers provide some of the earliest characterization of this condition in lactating cows. More recently, fatty liver has been associated with the ‘transition dairy cow’ and the unique nutritional, management, and metabolic needs of the dairy cow during the last 3 weeks of gestation and first 3 weeks of lactation. At calving, liver TG can exceed 20% of the weight of liver, and a liver TG content of greater than 40% has been reported for individual cows. The consequences of severe hepatic lipidosis are apparent; however, the consequences of mild hepatic liposis are more difficult to define. Approximately 50% of transition cows develop moderateto-severe fatty liver. Reducing the severity and incidence of this condition is a step toward improving the health and productivity of dairy cows. This article will outline the physiology and pathobiology of fatty liver in dairy cattle and describe the biochemistry underlying the development of this condition. Several excellent reviews that describe the classical nutrition and biochemistry associated with this disorder are available. Technologies and management strategies that reduce the incidence rate, severity, and duration of the occurrence of fatty liver in dairy cows continue to emerge. Current and emerging knowledge of this disorder and preventative strategies are discussed here.

How is Fatty Liver Diagnosed? Accumulation of fat in the liver does not usually produce any easily identifiable outward symptoms because it is deposited over a period of several days to weeks. The most common method for diagnosis of fatty liver requires

a cow-side surgery to obtain a sample of liver tissue. Cows do not react adversely to this minimally invasive procedure and the biopsy is usually obtained without a precise knowledge of the exact location within the liver but is assumed to be representative of the entire organ. The use of ultrasound to measure liver lipid content has been described recently by two independent groups and shows considerable promise as a noninvasive means of assessing fatty liver. Refinement of this technique will expand the possibilities for fatty liver diagnosis to larger groups of cows and broaden the assessment of nutritional and management strategies that influence fatty liver. Currently, studies to assess the impact of nutritional and management strategies on fatty liver in cow are limited due to the need for a biopsy sample in order to measure liver lipid content. The fat content of liver can be expressed as total liver lipid or total liver TG and requires approximately 100 mg of fresh tissue for analysis. Total liver lipid is extracted with organic solvents and the lipid content of the extract is determined quantitatively. TG in the extract is determined following saponification to release glycerol, which is then quantified as a measure of TG content. Other estimates of liver lipid content have been obtained from liver samples that have been fixed, sectioned, and stained. The fractional volume of lipid relative to total volume of liver cells, determined by microscopy, is then used to calculate liver lipid content. Liver TG content accurately reflects fatty liver and is the most common method used to describe the degree of lipid accumulation in the liver. A cowside test, based on the buoyancy of liver biopsy samples in aqueous solvents, has also been described but its use is restricted to gross classification of the condition. While biochemical analysis of liver lipid content is simple, it provides little information regarding the localization of fat within the liver or the relationship of fat to hepatocyte volume. As discussed below, the nature of TG depots within the hepatocytes and the location of TG within the liver acinus are used to classify hepatic steatosis in human disease states that include alcohol-induced fatty liver and nonalcoholic steatohepatitis. At calving, TG accumulates in the liver and may be coupled with decreases in other nonfat cellular components such as glycogen and liver protein. Measures of liver TG content should reflect changes in lipid and nonlipid cell

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components. Liver lipid content in dairy cows has been expressed as TG per gram of liver dry matter, as liver TG per gram of wet tissue, or liver TG per unit of DNA.

Prevalence of Fatty Liver Fatty liver in dairy cows was first classified as mild, moderate, and severe fatty liver corresponding to <5, 5–10, and >10 TG as a percentage of wet weight of the liver using a needle biopsy sample. The presence of 8–10% TG (% wet weight) in the liver sample relates to histological and functional differences. Ketosis is preceded by fatty liver and is the best recognized consequence of the condition. Healthy, mildly ketotic, and severely ketotic cows have a liver lipid content of 5, 8, and 17%, respectively, based on the analysis of fixed tissues using a light microscope and oil red O, a lipidspecific tissue stain. A liver lipid content of >17% TG of wet liver weight is classified as moderate-to-severe fatty liver based on 0.284 g liver dry weight per gram liver wet weight. Approximately 50% of multiparous cows in three trials at the University of Wisconsin had liver lipid contents >15% at calving and 30% had lipid contents >20%. Classification of liver TG as moderate to severe based on TG content per microgram DNA corresponds to values greater than 14 mg TG per mg liver DNA. Studies at Purdue University indicate that 26% of cows had greater than 14 mg TG per mg DNA in the liver at calving, but more than 70% of cows had liver TG above 14 mg per mg DNA by 28 days postcalving. Although differences may exist with regard to the timing of TG accumulation relative to calving using these methods, the data clearly indicate a high incidence of fatty liver in transition cows.

What Causes Fatty Liver? Hormonal changes associated with parturition, feed intake depression at calving, and increased energy demands initiate the release of nonesterified fatty acids (NEFAs) from adipose tissue. Fatty liver results if the uptake and esterification of NEFAs to TG exceed the capacity of the liver to further metabolize NEFAs or to secrete them as very-low-density lipoprotein (VLDL). Intensive liver biopsy sampling around calving indicates that elevated plasma NEFA levels precede TG accumulation in the liver. Attenuating the prepartum rise in NEFA levels serves to decrease the severity of fatty liver. On the other hand, the clearance of lipid from the liver as VLDL is controlled by the rate of VLDL synthesis and the degree of loading of the VLDL particles with TG. The rate of VLDL release in ruminants is inherently compromised compared to other species. The biochemistry and molecular biology underlying the inability of

ruminant liver to clear TG as VLDL is an area of active investigation. The basic biology of lipid metabolism in ruminants is not completely understood. Advances in this regard are necessary to identify therapeutic and nutritional interventions that will reduce the incidence and severity of fatty liver in periparturient dairy cattle. Some of the recent information on the basic processes controlling lipid clearance from the liver is highlighted here. The slow rate of TG export as VLDL is thought to be the main contributing factor leading to fatty liver in dairy cows. The VLDL particle is composed of four major lipid classes: phospholipids (mainly phosphatidylcholine), free cholesterol, TG, and cholesterol esters. The assembly and secretion of VLDL from the liver are dependent upon (1) the synthesis of apolipoprotein B (ApoB), the major structural protein associated with a stabilized VLDL particle; (2) ApoE, a component necessary for the VLDL assembly/secretion cascade; (3) the availability of lipids to form a surface coat (such as phosphatidylcholine and free cholesterol) and a neutral core (TG and cholesterol esters); and (4) the activity of microsomal triglyceride transfer protein (MTP) for VLDL filling. The MTP is a dedicated endoplasmic reticulumlocalized cofactor that is necessary for the assembly of ApoB with lipids. Within the endoplasmic reticulum, MTP functions with ApoB to form a small dense TG containing lipoprotein precursor particle. This initial phase of VLDL synthesis occurs coincident with the translation of the ApoB protein and its insertion into the endoplasmic reticulum and is referred to as the cotranslational phase of VLDL assembly. Within the endoplasmic reticulum, MTP also acts to transfer lipid to the VLDL precursor, known as the TG loading phase of VLDL synthesis, resulting in a mature VLDL particle for secretion. In the absence of MTP or sufficient TG, newly synthesized ApoB is delipidated and the ApoB protein associates with the inner leaf of the endoplasmic reticulum and is degraded. The relative abundance of MTP mRNA is elevated postcalving (154% of precalving values), but the mass of MTP protein is increased only 15% at calving. There is no correlation between hepatic MTP (mRNA and mass) and liver TG. Similarly, MTP activity and mass are not affected by nutritional status or insulin action and do not appear to be related to the rate of VLDL export. Likewise, a lack of coordinated change in ApoE with liver lipid concentrations during the periparturient period points to alternative limiting factors for triglyceride export from bovine liver. Free fatty acids in the liver stimulate VLDL assembly and TG secretion, but their effects depend on the physiological state and the experimental model. In primary hepatocytes from rats, oleic acid increased secretion of VLDL by increasing the translocation of ApoB across the endoplasmic reticulum. Dietary conditions that favor de novo hepatic fatty acid synthesis in nonruminants act

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to increase VLDL synthesis, whereas increased supply of preformed fatty acids acts to reduce VLDL output. It has been proposed that a high rate of esterification of fatty acids in bovine liver at calving acts to reduce the capacity for VLDL secretion and promotes fatty liver. Recent measures of change in the gene expression of MTP, ApoE, and ApoB-100 in the liver demonstrate a decrease in ApoB-100 during the periparturient period, which is consistent with decreased synthesis and/or secretion of VLDL from the liver. Some of the most effective therapies for combating the development of fatty liver in dairy cows may act by increasing the rate of synthesis of ApoB-100.

liver at calving, the prevalence of fatty liver in transition dairy cows is still a concern.

Risks Associated with Fatty Liver

Consequences of Fatty Liver

Fatty liver is implicated in the development of several metabolic disorders such as ketosis, impaired gluconeogenesis, impaired urea formation, increased incidence of mastitis, displaced abomasum, retained placenta, poor reproductive performance, and immune suppression. Fatty liver precedes the onset of clinical symptoms of ketosis. The prevalence of fatty liver can be reduced by common practices such as avoiding overconditioning at dryoff, maintaining body condition through the dry period, and managing the nutrition of cows during the transition to calving. Ideal condition scores, based on a 5-point scoring system, are in the range of 3.25–3.75 at dryoff and calving. While optimal management of body condition at dryoff may minimize the severity of fatty

The liver is geometrically organized into compartments or lobules, which are further configured to functional columns of 15–25 hepatocytes, which extend along sinusoids from the portal vein to the central vein called the liver acinus. Blood draining the rumen and intestines is collected in the portal vein, flows to the liver, and is dispersed through capillaries that flow across the cells of the liver acinus and emptied into the central vein of the liver lobule (Figures 1 and 2). The branches of the central vein coalesce to form the hepatic vein, which drains blood from the liver to the vena cava. Hepatocytes immediately adjacent to the branches of the portal vein (periportal hepatocytes) are therefore perfused with higher concentrations of oxygen and metabolites originating from the

Genetic Component There are several well-documented genetically linked disorders of hepatic lipid metabolism in humans and other species. Genetic analysis reveals a low heritability and repeatability of ketosis in dairy cows. These studies did not evaluate the genetic basis of fatty liver specifically, but due to the link between fatty liver and ketosis, one would conclude a lack of genetic basis for fatty liver in cows.

Figure 1 Arrangement of hepatocytes along a plate of cells within a lobule of liver. Blood enters a liver lobule through the portal vein (PV) and hepatic artery and passes through hepatic sinusoids to exit the lobule through a central vein (CV). Bile flows in the opposite direction and is collected via the bile ductule. Cells in close proximity to the portal vein of the liver lobule are termed periportal cells, whereas cells surrounding the central vein are termed pericentral cells. Fat infiltration commonly observed in dairy cattle at calving is initiated in the periportal zone and, with the progress in severity, it extends to the pericentral zone. Zonation of primary metabolic functions across liver acinus is indicated by the symbol X. VLDL, very-low-density lipoprotein.

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Figure 2 Arrangement of hepatocytes within the liver lobule and association of lobules. Plates of hepatocytes converge toward the central vein (CV) within lobules. The peripheral zone of lobules is demarcated by the portal triads, which consist of a branch of the hepatic artery, hepatic portal vein (PV), and a bile ductule. Blood flows from the portal triad along sinusoids between liver cells and is collected in the central vein (upper panel). Lipid infiltration is characterized by accumulation of lipid droplets first within cells in the periportal zone of the liver lobule and then extending toward the central vein (lower panel).

gastrointestinal tract. As a consequence, there is a marked functional and histological heterogeneity among cells that are located close to the portal vein (periportal hepatocytes) and cells located close to the central vein (pericentral hepatocytes) of the liver acinus. Within the liver acinus of nonruminants, betaoxidation of fatty acids, amino acid catabolism, ureagenesis, gluconeogenesis for the synthesis of both glucose and glycogen, cholesterol synthesis, and bile formation are predominantly located in the periportal zone, whereas glycolysis, glycogen synthesis, ketogenesis, glutamine formation, and metabolism of toxins are preferentially situated in the pericentral zone. Although the partitioning of biochemical functions within the microstructure of bovine liver has not been determined, it is reasonable to assume a heterogeneity in bovine that is similar to other species. Hepatic steatosis (fatty liver) is accompanied by many changes in the hepatic structure including compression of the hepatic sinusoids, mitochondrial damage, and decreased volume of the rough endoplasmic reticulum. Microscopic examination of liver tissue indicates the presence of fat droplets within hepatocytes. The

development of fatty liver associated with obesity, alcoholism, and diabetes in humans results in the accumulation of fat in cells in the periportal region of the liver, whereas the onset of acute fatty liver of pregnancy in humans results in fat deposition within pericentral hepatocytes. An accumulation of fat droplets proximal to the central vein has been noted during the development of fatty liver associated with calving in dairy cows. Decreased gluconeogenic capacity is a notable change that accompanies the fatty liver in vivo. A reduction in gluconeogenesis from propionate is also observed in bovine hepatocytes that are induced to be lipid filled in culture by incubation with oleic acid. Ammonia is toxic to mammalian cells, and one of the main functions of the liver is to detoxify ammonia to urea for excretion by the kidney. Bovine hepatocytes loaded with TG have reduced capacity to detoxify ammonia, leading to reduced capacity for other cellular functions including gluconeogenesis. Under normal conditions, the synthesis of glutamate in the liver acts as a high-affinity low-capacity scavenger system to detoxify ammonia that escapes

Diseases of Dairy Animals | Non-Infectious Diseases: Fatty Liver

ureagenesis. Pericentral cells of the liver display the highest rates of glutamate synthesis and serve as a backup system to the removal of ammonia that is not sequestered as urea in periportal hepatocytes. There appears to be little adaptation in urea synthetic capacity in the liver of transition dairy cows and the positive relationship between liver TG content, blood ammonia, and glutamine concentrations in transition cows, suggesting that the capacity for ammonia detoxification is overwhelmed. These findings have important implications with regard to overfeeding protein during late gestation in cows that are at risk for fatty liver due to overconditioning. The heterogeneity of fat deposition and metabolic activities within the liver acinus coupled with the progression of fatty liver in the central regions of the liver leads to a sequence of events that have progressive adverse effects on liver function and animal health.

Prevention and Treatment of Fatty Liver Several management practices are recognized that minimize the incidence and severity of fatty liver. Feeding practices that limit the rate and degree of fatty acid mobilization from adipose tissue, reduce the esterification of NEFAs as TG in liver, increase the export of TG from liver, and increase the oxidation of fatty acids all act to decrease fatty liver in dairy cows. It is recognized that strategies to reduce lipid accumulation in the liver must be implemented before calving in order to reduce the severity and incidence of lipid accumulation in the liver. Reducing the severity of feed intake depression at calving decreases the severity of fatty liver and tends to increase milk production. There has been a concerted effort toward improved feeding management strategies for transition dairy cows. Supplying adequate energy by increasing the energy density of transition cow diet may act to counter the effects of feed intake depression at calving. Circulating NEFAs are increased during late pregnancy due to depressed intake at calving, a diminished responsiveness to insulin in adipose tissue, and the subsequent mobilization of adipose tissue. Cows that experience health problems after calving had 18–20% lower prepartum intakes. When intake was maintained during the transition period by applying a force feeding protocol to rumenfistulated cows, the increase in NEFAs at calving was reduced in magnitude but was not eliminated. Recent experiments indicate a lack of response to increased protein density or type in the prepartum diet of multiparous cows; however, heifers approaching first calving may require additional protein for mammary development. Feeding excessive protein to prepartum cows may be detrimental due to the impaired capacity to detoxify ammonia.

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Increasing the energy density of the prepartum diets is beneficial in increasing liver glycogen content but not in reducing liver lipid. The ratio of TG to glycogen in the liver appears to be a predisposing factor for ketosis; therefore, increasing glycogen indirectly reduces the effects of fatty liver. Diets containing more energy may not reduce fatty liver but instead allow the cow to better cope with the condition. Feeding diets that have greater fermentative capacity in the rumen, such as steam-flaked corn, acts to decrease NEFA concentrations in the blood prior to calving and increase subsequent milk production. Greater energy intake will likely lead to physiological changes, such as increased insulin concentration, that reduce the mobilization of NEFAs from adipose tissue and promote glycogen storage in liver. Diets containing 1.62 Mcal of net energy of lactation (NEL) per kg are recommended, but energy content should be increased gradually beginning 2–3 weeks prior to calving to avoid adverse effects on rumen fermentation or predispose cows to other health disorders. Several compounds have been investigated for their ability to diminish the incidence and severity of fatty liver. Niacin feeding decreases blood ketones but does not appear to reduce liver TG content. Increasing the supply of precursors for glucose synthesis in liver using propylene glycol reduces liver TG. Part of the response to propylene glycol may be a consequence of increased blood insulin, reduced circulating NEFA levels, and increased liver glycogen. Ionophores, which act to alter rumen metabolism in favor of propionate production, appear to reduce the plasma ketones and subclinical ketosis under experimental conditions. Phosphatidylcholine, the major lipid component of the VLDL surface, may be limiting for VLDL assembly under some conditions in ruminants. Dietary choline deficiency accelerates ApoB degradation and decreases VLDL synthesis. Because choline is extensively degraded in the rumen and because choline and other methyl donors are critical to VLDL synthesis, the addition of rumen-protected choline has proved beneficial for transition dairy cows. Rumen-protected choline acts to reduce circulating NEFA concentrations and reduce the severity of liver lipid accumulation. Likewise, rumen-protected choline appears to enhance the rate of lipid clearance in cows that have been experimentally induced to express fatty liver. Choline is also necessary for carnitine synthesis, a necessary component of the translocation of fatty acids across the inner mitochondrial membrane mediated by carnitine palmitoyltransferase. Carnitine increases fatty acid oxidation in the bovine liver in vitro. Infusing carnitine into the abomasum of lactating dairy cows decreases plasma NEFA concentrations, leading to questions regarding the adequacy of carnitine and choline supply for fatty acid oxidation. Increasing the postruminal supply of L-carnitine reduces plasma NEFA

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concentrations and triglyceride accumulation in the liver by increasing hepatic oxidation of NEFAs. Feeding carnitine decreases total liver lipid in transition dairy cows, increases liver glycogen content in early lactation, and increases in vitro palmitate -oxidation by liver slices, an indicator of hepatic capacity for fatty acid oxidation. Hormonal interventions have been explored as a means of reducing liver lipids in dairy cows. Under normal conditions, plasma concentrations of somatotropin rise during late pregnancy, with a distinct peak at parturition and a decline to slightly elevated levels in early lactation. Somatotropin decreases the activity of key lipogenic enzymes in adipose tissue, apparently by opposing tissue response to insulin. Somatotropin also increases hepatic gluconeogenesis by activation of expression of the phosphoenolpyruvate gene, a pace-setting enzyme for gluconeogenesis in liver. Prepartum treatment with somatotropin increases plasma glucose and glucose disposal, and decreases plasma NEFAs prior to calving but does not alter liver TG content. The use of exogenous glucagon also holds promise as a therapy for fatty liver in dairy cows. Glucagon acts directly on the liver to increase gluconeogenesis. Experimental glucagon infusions in dairy cows decreased liver TG, increased blood glucose, and decreased blood ketones. Because the clearance of glucagon from blood is relatively rapid, the use of glucagon as a practical therapy for fatty liver will require a sustained delivery method. Treatment of transition cows with 15 mg glucagon per day reduces liver lipid content and decreases some of the detrimental effects of fatty liver on health and reproduction of dairy cows. Some of these effects are due to the ability of glucagon to simulate hepatic capacity for ammonia detoxification and gluconeogenesis through changes in the expression of key genes in these metabolic pathways. Although the balance of fatty acid metabolism and fatty acid storage as triglyceride is an essential component of fatty liver, it has been recognized recently that the profile of fatty acids presented to the liver may play a crucial role in determining the progression of this condition. The percentages of fatty acids within the liver are dramatically altered during adipose tissue lipolysis and these differences are more pronounced in cows that develop fatty liver. Likewise, the profile of fatty acids released from adipose tissue differs in cows that experience fatty liver. Recent evidence suggests a relationship between total liver lipid and fatty acid profile, in particular, an inverse relationship between long-chain unsaturated fatty acids and liver triglycerides has been demonstrated. Supporting data demonstrate that dry cows fed high levels of palmitic and oleic acid have increased hepatic fatty acid oxidation and reduced liver lipid in early lactation. The profile of fatty acids appears to be critical in this regard and has led to the introduction of feeding strategies that initiate metabolic priming in order

to permit cows to cope with body fat mobilization in early lactation. Although the mechanism of action of fatty acids as regulators of metabolism in ruminants is not completely characterized, it is likely to involve effects of specific fatty acids as controllers of gene promoters for enzymes in liver that catalyze key metabolic processes related to fatty acid oxidation and hepatic energy metabolism.

New Directions and the Role of ‘Omics’ in Understanding Fatty Liver Past approaches to understanding fatty liver have relied heavily on a reductionist approach, which is best exemplified by the focus on a causative dominant factor. In some cases, these have been linked to simple biomarkers such as reduced feed intake, increased mobilization of adipose tissue, and elevated blood NEFA levels. An implicit assumption in most studies is that fatty liver has a unique target, which would be most suitable for intervention. Although there are several examples where this reductionism has been tremendously helpful in understanding the etiology of fatty liver, there are other examples where this has not been the case. The advent of tools for genomics, proteomics, and metabolomics has provided an opportunity to simultaneously assess factors that at first glance effectively supersede the reductionist approach to understanding biology; however, when used effectively, these tools provide a greater opportunity to integrate the biology of the dairy cow on several levels with an ultimate goal of optimizing performance and minimizing the occurrence of metabolic diseases including fatty liver. The application of ‘omics’ tools to understanding the biology of fatty liver has been limited, but shows potential in helping to unravel this complex condition. Temporal transcript profiling using genomics tools that permit simultaneous analysis of over 6000 gene products in the liver of dairy cows indicates that fatty liver is linked to 85 genes that code for key enzymes associated with hepatic fatty acid oxidation, gluconeogenesis, and cholesterol synthesis. Currently, there are only a handful of reports of proteomic analysis of fatty liver in dairy cows, but these data identify downregulation of several enzymes involved in -oxidation, an increase in enzymes associated with ketogenesis, a reduction in enzymes associated with prevention of lipid peroxidation, and changes in lipid signaling molecules as well as key enzymes of gluconeogenesis, calcium homeostasis, and protein metabolism. Unfortunately, application of metabolomics to the study of fatty liver in cattle and other species has lagged behind genomics, but will be critical in validating the suspected control points in metabolism that are perturbed during the onset and progression of fatty liver. Regardless of the tools used to study this pathology, it is important to recognize that a complete cycle of hypothesis generation and testing is necessary to

Diseases of Dairy Animals | Non-Infectious Diseases: Fatty Liver

provide a complete understanding of the development, progression, and consequences of fatty liver in dairy cattle.

Conclusion Fatty liver is characterized by the deposition of lipid to approximately 3 times the normal concentrations. The incidence of fatty liver is greatest in the periparturient dairy cow, and more than 50% of all cows experience mild to severe fatty liver. A major factor leading to fatty liver is the inherent lack of ability of the liver of ruminants to export TG as VLDL. As a consequence, the progression of lipid deposition within the microstructure of liver leads to a progressive impairment of specific hepatic functions. These impairments are manifested as ketosis, reduced health, reduced productivity, impaired immune function, and increased risk of health disorders. The incidence and severity of fatty liver may be managed best using strategies that act in combination to limit adipose tissue mobilization at calving, enhance lipid oxidation in liver, and enhance release of lipid from liver for use by other tissues. See also: Analytical Methods: DNA-Based Assays. Body Condition: Effects on Health, Milk Production, and Reproduction. Diseases of Dairy Animals: Non-Infectious Diseases: Displaced Abomasum; Non-Infectious Diseases: Ketosis; Non-Infectious Diseases: Pregnancy Toxemia.

Further Reading Bertics SJ, Grummer RR, Cadorniga-Valino C, and Stoddard EE (1992) Effect of prepartum dry matter intake on liver triacylglycerol concentration and early lactation. Journal of Dairy Science 75: 1914–1922. Bobe G, Amin VR, Hippen AR, She P, Young JW, and Beitz DC (2008) Non-invasive detection of fatty liver in dairy cows by digital analyses of hepatic ultrasonograms. Journal of Dairy Research 75: 84–89. Cooke RF, Silva Del Rı´o N, Caraviello DZ, Bertics SJ, Ramos MH, and Grummer RR (2007) Supplemental choline for prevention and alleviation of fatty liver in dairy cattle. Journal of Dairy Science 90: 2413–2418.

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Drackley JK, Donkin SS, and Reynolds CK (2006) Major advances in fundamental dairy cattle nutrition. Journal of Dairy Science 89: 1324–1336. Gaal T, Reid IM, Collins RA, Roberts CJ, and Pike BV (1983) Comparison of biochemical and histological methods of estimating fat content of liver of dairy cows. Research in Veterinary Science 34: 245–248. Greenfield RB, Cecava MJ, Johnson TR, and Donkin SS (2000) Impact of dietary protein amount and rumen undegradability on intake, peripartum liver triglyceride, plasma metabolites, and milk production in transition dairy cattle. Journal of Dairy Science 83: 703–710. Grummer RR (1993) Etiology of lipid-related metabolic disorders in periparturient dairy cows. Journal of Dairy Science 76: 3882–3896. Gumucio JJ, Bilir BM, Moseley RH, and Berkowitz CM (1994) The biology of the liver cell plate. In: Arias IM, Boyer JL, and Fausto N (eds.) The Liver Biology and Pathobiology, 3rd edn., pp. 1143–1168. New York: Raven Press. Kang S and Davis RA (2000) Cholesterol and hepatic lipoprotein assembly and secretion. Biochimica et Biophysica Acta 1529: 223–230. Kuhla B, Albrecht D, Kuhla S, and Metges CC (2009) Proteome analysis of fatty liver in feed-deprived dairy cows reveals interaction of fuel sensing, calcium, fatty acid, and glycogen metabolism. Physiological Genomics 37: 88–98. Loor JJ, Everts RE, Bionaz M, et al. (2007) Nutrition-induced ketosis alters metabolic and signaling gene networks in liver of periparturient dairy cows. Physiological Genomics 32: 105–116. National Research Council (2001) Nutrient Requirements of Dairy Cattle, 7th revised edn. Washington, DC: National Academy Press. Reid IM (1980) Incidence and severity of fatty liver in dairy cows. The Veterinary Record 107: 281–284. Rukkwamsuk T, Geelen MJ, Kruip TA, and Wensing T (2000) Interrelation of fatty acid composition in adipose tissue, serum, and liver of dairy cows during the development of fatty liver postpartum. Journal of Dairy Science 83: 52–59. Strang BD, Bertics SJ, Grummer RR, and Armentano LE (1998) Effect of long-chain fatty acids on triglyceride accumulation, gluconeogenesis, and ureagenesis in bovine hepatocytes. Journal of Dairy Science 81: 728–739. Thijssen JM, Starke A, Weijers G, et al. (2008) Computer-aided B-mode ultrasound diagnosis of hepatic steatosis: A feasibility study. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control 55: 1343–1354. Uribe HA, Kennedy BW, Martin SW, and Kelton DF (1995) Genetic parameters for common health disorders of Holstein cows. Journal of Dairy Science 78(2): 421–430. Zhu LH, Armentano LE, Bremmer DR, Grummer RR, and Bertics SJ (2000) Plasma concentration of urea, ammonia, glutamine around calving, and the relation of hepatic triglyceride, to plasma ammonia removal of blood acid–base balance. Journal of Dairy Science 83: 734–740.