BACKGROUND
nonalcoholic fatty liver disease  can be a severe, progressive liver disease leading to the development of cirrhosis  <cit> .
obesity and type  <dig> diabetes are well-known risk factors for the development of nafld.
however, nafld is not rare in nonobese adults.
the result of examining over  <dig> nonobese individuals older than  <dig> years with nafld who participated in medical examinations shows that nafld can be considered an early predictor of metabolic disorders for the normal-weight population  <cit> .
nevertheless, the basis for nonobese hepatic steatosis remains uncertain, particularly for those who lack any metabolic syndromes.
several experimental animal models for nonobese nafld have been proposed.
among them, cholesterol-fed rabbits share several physiopathological features of nafld, like hyperlipidemia, but are devoid of insulin resistance or obesity  <cit> ; while overexpression of srebp-1a in spontaneously hypertensive rat models were nonobese animals with hypertension, hepatic steatosis, and the metabolic syndrome  <cit> .
all the above models are associated with metabolic syndrome in various degrees.
whether the basis of the "uncomplicated" nonobese hepatic steatosis is similar to hepatic steatosis complicated by obesity and/or metabolic syndrome remains unresolved.
hepatic steatosis is present in almost 50% of patients infected by hepatitis c virus , which therefore suggests it is an important contributor to nafld  <cit> .
we aimed to study the gene expression involved in lipid metabolism of an animal model of nonobese hepatic steatosis free from metabolic syndrome based on the conditional hcv core transgenic mice developed from our previous work.
liver from the  <dig> month old conditional hcv core transgenic mice on chow without doxycycline  showed that the severity of hepatic steatosis correlated with hcv core expression, peaked at the age of  <dig> months but diminished gradually  <cit> .
RESULTS
fatty liver evaluation
for the double transgenic mice , which express both the hcv core and tetracycline transactivator , oil red stain documented the existence of hepatic lipid vesicles that were compatible with hcv core protein in the parallel sections .
the severity of hepatic steatosis correlated with hcv core expression, and peaked at the age of  <dig> months, when the hepatic steatosis was microvesicular .
as the mouse aged, the microvesicular steatosis was replaced by macrovesicular steatosis  and dimished gradually .
the proportions of steatotic hepatocytes were approximately 20–30% in the liver of  <dig> month old mice on chow without dox, which were examined under low power field for h and e stain .
serum glucose, lipid, insulin and homeostatic model assessment for insulin resistance  evaluation
no significant differences in the serum glucose, lipid, insulin, or homa-ir levels between the dtm and single transgenic mice , which express tta alone, were noted.
no definitive abnormal levels were found in any of the mice.
systemic blood pressure  measurement
there was no significant difference in the sbp level between the dtm and stm.
no definitive abnormal levels were found in any of the mice.
microarray analyses
a total of  <dig> genes were evaluated.
of these, 97% remained after filtering for missing data and/or low expression levels.
significance analysis of microarrays  revealed no sex bias in gene expression from the microarray data.
for all of the  <dig> pairs, there were  <dig> genes that had m values  ≥  <dig>  and  <dig> genes that had m values ≤ - <dig>  among the  <dig> up-regulated genes, those involved in lipid metabolism were as follows: serum amyloid a <dig> , serum amyloid  <dig> , 7-dehydrocholesterol reductase  and 3-hydroxy-3-methylglutaryl-coenzyme a synthase  <dig> .
among the  <dig> down-regulated genes, those involved in lipid metabolism were as follows: apolipprotein ci , apolipoprotein aii , fatty acid binding protein  <dig>  liver , acyl-coa thioesterase i and apolipoprotein e  .
gene functional analysis for the microarray data showed that only the acute-phase response had a significant p value and false discovery rate  .
†student's t-test.
‡adjusted p-value for benjamini and hochberg method fdr.
quantitative real-time polymerase chain reaction
our q-rt-pcr data were regarded as significant at m  ≥  <dig>  or ≤ - <dig> .
for the four up-regulated genes involved in lipid metabolism, q-rt-pcr of all the  <dig> pairs showed only hmgcs <dig> had m value higher than  <dig> ; for the five down-regulated genes involved in lipid metabolism, apo ci, apo aii, acot <dig> and fabpl showed m values less than - <dig> .
the mean and standard deviation of m values of q-rt-pcr for the various genes are listed in table  <dig>
pathway classification
arrayxpath identified  <dig> out of  <dig> input elements in  <dig> out of  <dig> biocarta pathways.
the pathways are shown in table  <dig>  among the  <dig> pathways,  <dig> pathways showed significance with both p-values and q-values less than  <dig> .
the sterol-regulatory element-binding protein  pathway composed of srebf <dig>  srebf <dig>  mbpts <dig>  scap, ldlr and hmgcs <dig> is involved in lipid metabolism.
hmgcs <dig> activation was identified in the current study.
identified node: matched nodes/unique nodes in pathway .
discussion
we developed an animal model of nonobese hepatic steatosis based on mice conditionally expressing the hcv core protein.
doxycycline  chow, which contained an analog of tetracycline, was used to regulate the transgene expression.
dox is regarded as a steatogenic drug by means of inhibiting mitochondrial fatty acid beta-oxidation  <cit> .
to avoid the bias of drug-related hepatic steatosis, we prescribed both the dtm and stm with the same course of dox administration.
we also ensured that the hepatic steatosis was due to expression of the hcv core transgene by comparing the liver biopsies from the dtm and stm.
the former did show significant hepatic steatosis compared to the latter.
hcv core protein is known to play crucial roles in host cell lipid metabolism both in vitro and in vivo  <cit> .
gene expression profiles have been reported after hcv core expression in primary hepatocytes  <cit> , hepatoma cell lines,  <cit>  and yeast cells  <cit> .
however, the data obtained for hepatic steatosis in vitro might not mirror that obtained in vivo.
the expression of hcv core leads to progressive hepatic steatosis in several lines of constitutive transgenic mice  <cit> .
hepatocellular carcinoma  also results in some of these older mice due to oxidative stress  <cit> .
thus, in those constitutive transgenic mice, hepatic steatosis is a relay of hcc and may be the sequel of carcinogenic gene expression.
in the current model, hcv core expression was robust and paralleled the degree of hepatic steatosis.
both core expression and hepatic steatosis peaked at  <dig> months but diminished gradually afterward.
we did not find hcc in these mice, regardless of their age, partly due to hcv core-related, augmented hepatocellular apoptosis  <cit> .
therefore, because we established the exact timing of peak hepatic steatosis emergence  and these mice did not develop hcc, we propose that this is a valid model to study the basis of hepatic steatosis without bias.
none of the transgenic mice showed definitively abnormal serum glucose, lipid, insulin, or homa-ir levels, and the blood pressure remained normal.
the gene expression profiles of nondiabetic and diabetic ob/ob mice reported by lan et al.
suggest that increased hepatic lipogenic capacity protects the ob/ob mice from the development of type  <dig> diabetes  <cit> .
cumulatively, these observations indicate a lack of metabolic syndrome in these conditional hcv core mice that may have resulted from an only modest level of steatosis, which protects these mice from diabetes but is not sufficiently vigorous to cause metabolic syndrome.
gene functional analysis of the microarray data showed that only the genes for an acute-phase response had significant p values and fdr .
these results are compatible with the observation that hcv core expression leads to augmented oxidative stress and hepatocellular apoptosis, but not subsequent hepatic inflammation and fibrosis in dtm  <cit> .
however, several genes involved in mitochondrial function , the immune reaction , coagulation , the cell cycle , cell differentiation , cell proliferation , apoptosis , angiogenesis , and cytochrome p <dig> function  were also regulated in the livers of dtm .
at the basis of gene expression, the data did not conclusively explain why those mice did not develop hcc.
for example, the downregulation of onecut <dig> and upregulation of ifitm <dig> might inhibit cell proliferation  <cit> , whereas the downregulation of gadd45g might enhance tumor cell growth  <cit> .
several attempts were performed to approach the gene expression for human nafld.
a study on microarray analyses including  <dig> human liver samples showed that mitochondrial alterations play a major role in the development of steatosis per se and the activation of inflammatory pathways is present at a very early stage of steatosis, even if no morphological sign of inflammation is observed  <cit> .
in addition, the analyses of global hepatic gene expression in histologically progressive nonalcoholic steatohepatitis revealed down-regulated genes for maintaining mitochondrial function and up-regulated genes of c <dig> and hepatocyte-derived fibrinogen-related protein  <cit> .
therefore, mitochondrial function alteration and c3-implicated immune reaction/inflammation  are likely to contribute at least partly to the hepatic steatosis in the current transgenic mice based on human nafld gene expression studies.
cyp4a enzymes were identified as initiators of oxidative stress in the liver of mice fed a methionine- and choline-deficient  diet, while the role of cyp4a <dig> in hepatic steatosis demands further clarification  <cit> .
we focused our analysis of the microarray data, q-rt-pcr, and the gene nodal classifications on lipid metabolism.
the livers of dtm showed one up-regulated gene, hmgcs1; four down-regulated genes, apo ci, apo aii, acot <dig>  and fabpl; and one activated pathway, srebp-mediated control of lipid synthesis.
hcv core expression decreased hepatic lipoprotein secretion and caused steatosis as shown using a line of constitutive hcv core transgenic mice  <cit> .
by transfecting cell lines with hcv core plasmids, barba et al.
showed the colocalization of hcv core protein and apo aii  <cit> .
the direct binding of hcv core with apo aii was also documented  <cit> .
moreover, hepatic human apo aii expression in hcv core protein/apo aii-/- transgenic mice diminished intrahepatic core protein accumulation, whereas the converse scenario is highly possible, although uncertain, based on our result  <cit> .
little data directly address the relationships between hcv core-related steatosis and apo ci.
the infectivity of hcv pseudotyped retroviral particles is enhanced by apo ci  <cit> .
this observation suggests that a correlation may exist between apo ci and the hcv core because the hcv core protein plays an important role in infectivity.
acot <dig> is an enzyme that hydrolyzes long-chain acyl-coas of c-c-coa in chain length to the free fatty acid and coenzyme a   <cit> .
the potency of acot <dig> may serve to modulate intracellular concentrations of acyl-coas, free fatty acids, and coa to affect various cellular functions, including lipid metabolism  <cit> .
the downregulation of acot <dig> likely leads to increased acyl-coa and subsequent beta oxidation, which might counter-regulate hepatic steatosis secondary to hcv core expression  <cit> .
in regard to the srebp pathway, several in vivo systems have documented its association with hcv or the hcv core protein.
during the early stages of acute hcv infection, chimpanzees that develop either transient or sustained clearance of virus show activated genes involved in the srebp pathway as determined by genome-wide transcriptional analyses  <cit> .
hcv infection is also known to induce the proteolytic cleavage and phosphorylation of srebps via oxidative stress  <cit> .
furthermore, genes related to fatty acid biosynthesis and srebp-1c promoter activity are up-regulated by the hcv core protein in cell lines and constitutive hcv core transgenic mice livers in a pa28gamma-dependent manner  <cit> .
our results demonstrate that aside from srebps themselves, hmgcs <dig>  the crucial enzyme for the srebp pathway, also plays some role in hcv core related hepatic steatosis.
whether hmgcs <dig> activation is specific to hcv core expression or is subsequent to hepatic steatosis demands further clarification.
to our knowledge, fabp <dig> has not been reported as being responsible for hcv core-related steatosis.
the primary role of all the fabp family members is the regulation of fatty acid uptake and intracellular transport  <cit> .
the fabp <dig> gene is turned on by long-chain fatty acids and nonmetabolized fatty acids in a physiologically relevant manner  <cit> .
fabp <dig> and microsomal triglyceride transfer protein  are known to shunt fatty acids cooperatively into de novo synthesized glycerolipids and transfer lipids into very low-density lipoprotein , respectively, which act together to maintain hepatic lipid homeostasis  <cit> .
it is likely that either the hcv core leads to hepatic steatosis by means of modulating fabpl gene expression to inhibit mtp protein activity and vldl secretion  <cit>  or that downregulation of fabpl is a nonspecific phenomenon secondary to hepatic steatosis.
CONCLUSIONS
we developed an animal model of nonobese hepatic steatosis with the transgenic expression of the hcv core protein.
these mice were free of metabolic syndrome.
the degree of hepatic steatosis paralleled the expression of the hcv core protein, and both core protein expression and steatosis diminished with time.
gene expression analysis of liver rna from the transgenic mice showed that several genes involved in lipid transport, mitochondrial function, the immune reaction, and inflammation were either up- or down-regulated.
the srebp pathway was also activated as shown by the upregulation of the hmgcs <dig> gene.
our model lends itself to studying the gene expression patterns in nonobese hepatic steatosis, especially those associated with hcv infection.

 nonalcoholic fatty liver disease can be a severe, progressive liver disease leading to the development of cirrhosis. obesity and type diabetes are well-known risk factors for the development of nafld. however, nafld is not rare in nonobese adults. the result of examining over nonobese individuals older than years with nafld who participated in medical examinations shows that nafld can be considered an early predictor of metabolic disorders for the normal-weight population. nevertheless, the basis for nonobese hepatic steatosis remains uncertain, particularly for those who lack any metabolic syndromes. several experimental animal models for nonobese nafld have been proposed. among them, cholesterol-fed rabbits share several physiopathological features of nafld, like hyperlipidemia, but are devoid of insulin resistance or obesity; while overexpression of srebp-1a in spontaneously hypertensive rat models were nonobese animals with hypertension, hepatic steatosis, and the metabolic syndrome. all the above models are associated with metabolic syndrome in various degrees. whether the basis of the "uncomplicated" nonobese hepatic steatosis is similar to hepatic steatosis complicated by obesity and/or metabolic syndrome remains unresolved. hepatic steatosis is present in almost 50% of patients infected by hepatitis c virus, which therefore suggests it is an important contributor to nafld. we aimed to study the gene expression involved in lipid metabolism of an animal model of nonobese hepatic steatosis free from metabolic syndrome based on the conditional hcv core transgenic mice developed from our previous work. liver from the month old conditional hcv core transgenic mice on chow without doxycycline showed that the severity of hepatic steatosis correlated with hcv core expression, peaked at the age of months but diminished gradually.  fatty liver evaluation for the double transgenic mice, which express both the hcv core and tetracycline transactivator, oil red stain documented the existence of hepatic lipid vesicles that were compatible with hcv core protein in the parallel sections. the severity of hepatic steatosis correlated with hcv core expression, and peaked at the age of months, when the hepatic steatosis was microvesicular. as the mouse aged, the microvesicular steatosis was replaced by macrovesicular steatosis and dimished gradually. the proportions of steatotic hepatocytes were approximately 20–30% in the liver of month old mice on chow without dox, which were examined under low power field for h and e stain. serum glucose, lipid, insulin and homeostatic model assessment for insulin resistance evaluation no significant differences in the serum glucose, lipid, insulin, or homa-ir levels between the dtm and single transgenic mice, which express tta alone, were noted. no definitive abnormal levels were found in any of the mice. systemic blood pressure measurement there was no significant difference in the sbp level between the dtm and stm. no definitive abnormal levels were found in any of the mice. microarray analyses a total of genes were evaluated. of these, 97% remained after filtering for missing data and/or low expression levels. significance analysis of microarrays revealed no sex bias in gene expression from the microarray data. for all of the pairs, there were genes that had m values ≥ and genes that had m values ≤ - among the up-regulated genes, those involved in lipid metabolism were as follows: serum amyloid a, serum amyloid, 7-dehydrocholesterol reductase and 3-hydroxy-3-methylglutaryl-coenzyme a synthase. among the down-regulated genes, those involved in lipid metabolism were as follows: apolipprotein ci, apolipoprotein aii, fatty acid binding protein liver, acyl-coa thioesterase i and apolipoprotein e. gene functional analysis for the microarray data showed that only the acute-phase response had a significant p value and false discovery rate. †student's t-test. ‡adjusted p-value for benjamini and hochberg method fdr. quantitative real-time polymerase chain reaction our q-rt-pcr data were regarded as significant at m ≥ or ≤ -. for the four up-regulated genes involved in lipid metabolism, q-rt-pcr of all the pairs showed only hmgcs had m value higher than; for the five down-regulated genes involved in lipid metabolism, apo ci, apo aii, acot and fabpl showed m values less than -. the mean and standard deviation of m values of q-rt-pcr for the various genes are listed in table pathway classification arrayxpath identified out of input elements in out of biocarta pathways. the pathways are shown in table among the pathways, pathways showed significance with both p-values and q-values less than. the sterol-regulatory element-binding protein pathway composed of srebf srebf mbpts scap, ldlr and hmgcs is involved in lipid metabolism. hmgcs activation was identified in the current study. identified node: matched nodes/unique nodes in pathway. discussion we developed an animal model of nonobese hepatic steatosis based on mice conditionally expressing the hcv core protein. doxycycline chow, which contained an analog of tetracycline, was used to regulate the transgene expression. dox is regarded as a steatogenic drug by means of inhibiting mitochondrial fatty acid beta-oxidation. to avoid the bias of drug-related hepatic steatosis, we prescribed both the dtm and stm with the same course of dox administration. we also ensured that the hepatic steatosis was due to expression of the hcv core transgene by comparing the liver biopsies from the dtm and stm. the former did show significant hepatic steatosis compared to the latter. hcv core protein is known to play crucial roles in host cell lipid metabolism both in vitro and in vivo. gene expression profiles have been reported after hcv core expression in primary hepatocytes, hepatoma cell lines, and yeast cells. however, the data obtained for hepatic steatosis in vitro might not mirror that obtained in vivo. the expression of hcv core leads to progressive hepatic steatosis in several lines of constitutive transgenic mice. hepatocellular carcinoma also results in some of these older mice due to oxidative stress. thus, in those constitutive transgenic mice, hepatic steatosis is a relay of hcc and may be the sequel of carcinogenic gene expression. in the current model, hcv core expression was robust and paralleled the degree of hepatic steatosis. both core expression and hepatic steatosis peaked at months but diminished gradually afterward. we did not find hcc in these mice, regardless of their age, partly due to hcv core-related, augmented hepatocellular apoptosis. therefore, because we established the exact timing of peak hepatic steatosis emergence and these mice did not develop hcc, we propose that this is a valid model to study the basis of hepatic steatosis without bias. none of the transgenic mice showed definitively abnormal serum glucose, lipid, insulin, or homa-ir levels, and the blood pressure remained normal. the gene expression profiles of nondiabetic and diabetic ob/ob mice reported by lan et al. suggest that increased hepatic lipogenic capacity protects the ob/ob mice from the development of type diabetes. cumulatively, these observations indicate a lack of metabolic syndrome in these conditional hcv core mice that may have resulted from an only modest level of steatosis, which protects these mice from diabetes but is not sufficiently vigorous to cause metabolic syndrome. gene functional analysis of the microarray data showed that only the genes for an acute-phase response had significant p values and fdr. these results are compatible with the observation that hcv core expression leads to augmented oxidative stress and hepatocellular apoptosis, but not subsequent hepatic inflammation and fibrosis in dtm. however, several genes involved in mitochondrial function, the immune reaction, coagulation, the cell cycle, cell differentiation, cell proliferation, apoptosis, angiogenesis, and cytochrome p function were also regulated in the livers of dtm. at the basis of gene expression, the data did not conclusively explain why those mice did not develop hcc. for example, the downregulation of onecut and upregulation of ifitm might inhibit cell proliferation, whereas the downregulation of gadd45g might enhance tumor cell growth. several attempts were performed to approach the gene expression for human nafld. a study on microarray analyses including human liver samples showed that mitochondrial alterations play a major role in the development of steatosis per se and the activation of inflammatory pathways is present at a very early stage of steatosis, even if no morphological sign of inflammation is observed. in addition, the analyses of global hepatic gene expression in histologically progressive nonalcoholic steatohepatitis revealed down-regulated genes for maintaining mitochondrial function and up-regulated genes of c and hepatocyte-derived fibrinogen-related protein. therefore, mitochondrial function alteration and c3-implicated immune reaction/inflammation are likely to contribute at least partly to the hepatic steatosis in the current transgenic mice based on human nafld gene expression studies. cyp4a enzymes were identified as initiators of oxidative stress in the liver of mice fed a methionine- and choline-deficient diet, while the role of cyp4a in hepatic steatosis demands further clarification. we focused our analysis of the microarray data, q-rt-pcr, and the gene nodal classifications on lipid metabolism. the livers of dtm showed one up-regulated gene, hmgcs1; four down-regulated genes, apo ci, apo aii, acot and fabpl; and one activated pathway, srebp-mediated control of lipid synthesis. hcv core expression decreased hepatic lipoprotein secretion and caused steatosis as shown using a line of constitutive hcv core transgenic mice. by transfecting cell lines with hcv core plasmids, barba et al. showed the colocalization of hcv core protein and apo aii. the direct binding of hcv core with apo aii was also documented. moreover, hepatic human apo aii expression in hcv core protein/apo aii-/- transgenic mice diminished intrahepatic core protein accumulation, whereas the converse scenario is highly possible, although uncertain, based on our result. little data directly address the relationships between hcv core-related steatosis and apo ci. the infectivity of hcv pseudotyped retroviral particles is enhanced by apo ci. this observation suggests that a correlation may exist between apo ci and the hcv core because the hcv core protein plays an important role in infectivity. acot is an enzyme that hydrolyzes long-chain acyl-coas of c-c-coa in chain length to the free fatty acid and coenzyme a. the potency of acot may serve to modulate intracellular concentrations of acyl-coas, free fatty acids, and coa to affect various cellular functions, including lipid metabolism. the downregulation of acot likely leads to increased acyl-coa and subsequent beta oxidation, which might counter-regulate hepatic steatosis secondary to hcv core expression. in regard to the srebp pathway, several in vivo systems have documented its association with hcv or the hcv core protein. during the early stages of acute hcv infection, chimpanzees that develop either transient or sustained clearance of virus show activated genes involved in the srebp pathway as determined by genome-wide transcriptional analyses. hcv infection is also known to induce the proteolytic cleavage and phosphorylation of srebps via oxidative stress. furthermore, genes related to fatty acid biosynthesis and srebp-1c promoter activity are up-regulated by the hcv core protein in cell lines and constitutive hcv core transgenic mice livers in a pa28gamma-dependent manner. our results demonstrate that aside from srebps themselves, hmgcs the crucial enzyme for the srebp pathway, also plays some role in hcv core related hepatic steatosis. whether hmgcs activation is specific to hcv core expression or is subsequent to hepatic steatosis demands further clarification. to our knowledge, fabp has not been reported as being responsible for hcv core-related steatosis. the primary role of all the fabp family members is the regulation of fatty acid uptake and intracellular transport. the fabp gene is turned on by long-chain fatty acids and nonmetabolized fatty acids in a physiologically relevant manner. fabp and microsomal triglyceride transfer protein are known to shunt fatty acids cooperatively into de novo synthesized glycerolipids and transfer lipids into very low-density lipoprotein, respectively, which act together to maintain hepatic lipid homeostasis. it is likely that either the hcv core leads to hepatic steatosis by means of modulating fabpl gene expression to inhibit mtp protein activity and vldl secretion or that downregulation of fabpl is a nonspecific phenomenon secondary to hepatic steatosis.  we developed an animal model of nonobese hepatic steatosis with the transgenic expression of the hcv core protein. these mice were free of metabolic syndrome. the degree of hepatic steatosis paralleled the expression of the hcv core protein, and both core protein expression and steatosis diminished with time. gene expression analysis of liver rna from the transgenic mice showed that several genes involved in lipid transport, mitochondrial function, the immune reaction, and inflammation were either up- or down-regulated. the srebp pathway was also activated as shown by the upregulation of the hmgcs gene. our model lends itself to studying the gene expression patterns in nonobese hepatic steatosis, especially those associated with hcv infection. 
gene expression analyses revealed sterol-regulatory element-binding protein pathway activation and dysregulation of the following genes involved in lipid metabolism: 3-hydroxy-3-methylglutaryl-coenzyme a synthase apolipoprotein aii, apolipoprotein ci, acyl-coa thioesterase i, and fatty acid binding protein 1; in mitochondrial function: solute carrier family member and cytochrome c oxidase subunit ii; in immune reaction: complement component lymphocyte antigen complex, locus a, lymphocyte antigen complex, locus c, lymphocyte antigen complex, locus d, and lymphocyte antigen complex, locus e. because the gene expression patterns of nonobese hepatic steatosis in affected patients remain unclear, we sought to explore these patterns using an animal model of nonobese hepatic steatosis. microarray analyses and reverse-transcription polymerase chain reaction were performed using liver samples of both the double transgenic mice, which express both the hcv core and tta, and single transgenic mice, which express tta alone, at months of age. some genes of lipid metabolism, mitochondrial function, and immune reaction and the srebp pathway are involved in hcv core-related, nonobese, modest hepatic steatosis. no significant differences were observed in the serum glucose, lipid content, or blood pressure levels between the dtm and stm. we developed mice that conditionally express the hepatitis c virus core protein regulated by the tetracycline transactivator. serum glucose, lipid levels, and systemic blood pressure were also measured.
 because the gene expression patterns of nonobese hepatic steatosis in affected patients remain unclear, we sought to explore these patterns using an animal model of nonobese hepatic steatosis. methods we developed mice that conditionally express the hepatitis c virus core protein regulated by the tetracycline transactivator. microarray analyses and reverse-transcription polymerase chain reaction were performed using liver samples of both the double transgenic mice, which express both the hcv core and tta, and single transgenic mice, which express tta alone, at months of age. functional categories of genes with altered expression were classified using gene ontology programs. serum glucose, lipid levels, and systemic blood pressure were also measured.  approximately 20–30% of hepatocytes from the dtm were steatotic. no significant differences were observed in the serum glucose, lipid content, or blood pressure levels between the dtm and stm. gene expression analyses revealed sterol-regulatory element-binding protein pathway activation and dysregulation of the following genes involved in lipid metabolism: 3-hydroxy-3-methylglutaryl-coenzyme a synthase apolipoprotein aii, apolipoprotein ci, acyl-coa thioesterase i, and fatty acid binding protein 1; in mitochondrial function: solute carrier family member and cytochrome c oxidase subunit ii; in immune reaction: complement component lymphocyte antigen complex, locus a, lymphocyte antigen complex, locus c, lymphocyte antigen complex, locus d, and lymphocyte antigen complex, locus e.  some genes of lipid metabolism, mitochondrial function, and immune reaction and the srebp pathway are involved in hcv core-related, nonobese, modest hepatic steatosis. 