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Keratin 8 overexpression promotes mouse Mallory body formation.

Nakamichi I, Toivola DM, Strnad P, Michie SA, Oshima RG, Baribault H, Omary MB - J. Cell Biol. (2005)

Bottom Line: Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression.MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford University, and Veterans Affairs Palo Alto Health Care System, CA 94305, USA.

ABSTRACT
Keratins 8 and 18 (K8/18) are major constituents of Mallory bodies (MBs), which are hepatocyte cytoplasmic inclusions seen in several liver diseases. K18- but not K8- or heterozygous mice form MBs, which indicates that K8 is important for MB formation. Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression. We used transgenic mice that overexpress K8, K18, or K8/18 to test the importance of K8 and/or K18 in MB formation. MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Livers of young K8 or K8/K18 overexpressors had no histological abnormalities despite increased keratin protein and phosphorylation. In aging mice, only K8-overexpressing livers spontaneously developed small "pre-MB" aggregates. Only K8-overexpressing young mice are highly susceptible to MB formation after short-term DDC feeding. Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation. K8 overexpression is sufficient to form pre-MB and primes animals to accumulate MBs upon DDC challenge, which may help explain MB formation in human liver diseases.

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Summary of MB formation in different mouse genotypes, and a model of MB formation depending on K8 versus K18 protein levels. (A) Summary of MB formation under basal (i.e., spontaneous) and DDC feeding (i.e., induced) conditions in keratin mouse models. (B) A model depicting two types of liver injury: (1) MB-associated liver injury that progressively leads to MB formation in association with keratin overexpression (K8 > K18) and keratin hyperphosphorylation; and (2) non–MB-associated liver injury that results in keratin overexpression (K8 = K18 or K18 > K8) or maintenance of keratin levels coupled with keratin hyperphosphorylation. NASH, nonalcoholic steatohepatitis.
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fig5: Summary of MB formation in different mouse genotypes, and a model of MB formation depending on K8 versus K18 protein levels. (A) Summary of MB formation under basal (i.e., spontaneous) and DDC feeding (i.e., induced) conditions in keratin mouse models. (B) A model depicting two types of liver injury: (1) MB-associated liver injury that progressively leads to MB formation in association with keratin overexpression (K8 > K18) and keratin hyperphosphorylation; and (2) non–MB-associated liver injury that results in keratin overexpression (K8 = K18 or K18 > K8) or maintenance of keratin levels coupled with keratin hyperphosphorylation. NASH, nonalcoholic steatohepatitis.

Mentions: Our study provides direct evidence that perturbations in individual keratin protein levels, which occur during liver injury, account for MB formation. Overexpression of individual K8 or K18 or combined K8/18 indicated that an increase in the ratio of K8 to K18 is a key ingredient for MB formation. Findings in this study and those previously described for K8 −/− or K8 +/− (which do not form MBs even when challenged) and K18 −/− mice (which form MB-like structures spontaneously) are summarized in Fig. 5 A. Collectively, these data indicate that the availability of “excess” K8 acts as a nidus for hepatocyte MB formation and that excess K18 or K8/18 are well tolerated to the extent that they do not lead to MB formation. Excess K8 requires additional stimuli that ultimately induce MB formation because K18- (Magin et al., 1998) and K8 mice (Fig. 2) develop MBs only at an old age. Additional stimuli may include aging and its related oxidative damage (Holbrook and Ikeyama, 2002) or chronic toxic liver injury, such as DDC in mice or alcohol or nonalcoholic steatohepatitis in humans (Fig. 5 B). Keratin overexpression is well tolerated under basal conditions (Fig. 1) and does not significantly affect susceptibility to liver injury in DDC-fed mice regardless of whether MBs form in a prominent (K8 mice) or limited (WT, K18, or K8/18 mice) fashion (Figs. 3 and 4). Therefore, in DDC-related injuries, a propensity for MB formation is a reflection of preferential K8 overexpression coupled with additional stimuli, but it does not correlate with the extent of liver injury per se. Interestingly, the formation of K8-containing aggregates also occurs in a physiological context during early mouse embryogenesis when K8 and K7 but not type I keratin proteins are expressed (Lu et al., 2005).


Keratin 8 overexpression promotes mouse Mallory body formation.

Nakamichi I, Toivola DM, Strnad P, Michie SA, Oshima RG, Baribault H, Omary MB - J. Cell Biol. (2005)

Summary of MB formation in different mouse genotypes, and a model of MB formation depending on K8 versus K18 protein levels. (A) Summary of MB formation under basal (i.e., spontaneous) and DDC feeding (i.e., induced) conditions in keratin mouse models. (B) A model depicting two types of liver injury: (1) MB-associated liver injury that progressively leads to MB formation in association with keratin overexpression (K8 > K18) and keratin hyperphosphorylation; and (2) non–MB-associated liver injury that results in keratin overexpression (K8 = K18 or K18 > K8) or maintenance of keratin levels coupled with keratin hyperphosphorylation. NASH, nonalcoholic steatohepatitis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171301&req=5

fig5: Summary of MB formation in different mouse genotypes, and a model of MB formation depending on K8 versus K18 protein levels. (A) Summary of MB formation under basal (i.e., spontaneous) and DDC feeding (i.e., induced) conditions in keratin mouse models. (B) A model depicting two types of liver injury: (1) MB-associated liver injury that progressively leads to MB formation in association with keratin overexpression (K8 > K18) and keratin hyperphosphorylation; and (2) non–MB-associated liver injury that results in keratin overexpression (K8 = K18 or K18 > K8) or maintenance of keratin levels coupled with keratin hyperphosphorylation. NASH, nonalcoholic steatohepatitis.
Mentions: Our study provides direct evidence that perturbations in individual keratin protein levels, which occur during liver injury, account for MB formation. Overexpression of individual K8 or K18 or combined K8/18 indicated that an increase in the ratio of K8 to K18 is a key ingredient for MB formation. Findings in this study and those previously described for K8 −/− or K8 +/− (which do not form MBs even when challenged) and K18 −/− mice (which form MB-like structures spontaneously) are summarized in Fig. 5 A. Collectively, these data indicate that the availability of “excess” K8 acts as a nidus for hepatocyte MB formation and that excess K18 or K8/18 are well tolerated to the extent that they do not lead to MB formation. Excess K8 requires additional stimuli that ultimately induce MB formation because K18- (Magin et al., 1998) and K8 mice (Fig. 2) develop MBs only at an old age. Additional stimuli may include aging and its related oxidative damage (Holbrook and Ikeyama, 2002) or chronic toxic liver injury, such as DDC in mice or alcohol or nonalcoholic steatohepatitis in humans (Fig. 5 B). Keratin overexpression is well tolerated under basal conditions (Fig. 1) and does not significantly affect susceptibility to liver injury in DDC-fed mice regardless of whether MBs form in a prominent (K8 mice) or limited (WT, K18, or K8/18 mice) fashion (Figs. 3 and 4). Therefore, in DDC-related injuries, a propensity for MB formation is a reflection of preferential K8 overexpression coupled with additional stimuli, but it does not correlate with the extent of liver injury per se. Interestingly, the formation of K8-containing aggregates also occurs in a physiological context during early mouse embryogenesis when K8 and K7 but not type I keratin proteins are expressed (Lu et al., 2005).

Bottom Line: Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression.MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford University, and Veterans Affairs Palo Alto Health Care System, CA 94305, USA.

ABSTRACT
Keratins 8 and 18 (K8/18) are major constituents of Mallory bodies (MBs), which are hepatocyte cytoplasmic inclusions seen in several liver diseases. K18- but not K8- or heterozygous mice form MBs, which indicates that K8 is important for MB formation. Early stages in MB genesis include K8/18 hyperphosphorylation and overexpression. We used transgenic mice that overexpress K8, K18, or K8/18 to test the importance of K8 and/or K18 in MB formation. MBs were induced by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Livers of young K8 or K8/K18 overexpressors had no histological abnormalities despite increased keratin protein and phosphorylation. In aging mice, only K8-overexpressing livers spontaneously developed small "pre-MB" aggregates. Only K8-overexpressing young mice are highly susceptible to MB formation after short-term DDC feeding. Thus, the K8 to K18 ratio, rather than K8/18 overexpression by itself, plays an essential role in MB formation. K8 overexpression is sufficient to form pre-MB and primes animals to accumulate MBs upon DDC challenge, which may help explain MB formation in human liver diseases.

Show MeSH
Related in: MedlinePlus