Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice

PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT (Ppara+/+), total body Ppara-null (Ppara−/−), and hepatocyte-specific Ppara-null (PparaΔHep) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in PparaΔHep versus Ppara−/− mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in PparaΔHep mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in Ppara−/− mice. In PparaΔHep mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT (Ppara+/+), total body Ppara-null (Ppara−/−), and hepatocyte-specific Ppara-null (PparaΔHep) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in PparaΔHep versus Ppara−/− mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in PparaΔHep mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in Ppara−/− mice. In PparaΔHep mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. PPARα (PPARA) is considered a major regulator of systemic lipid homeostasis and, consequently, the prolonged fasting response. PPARA is a ligand-activated nuclear receptor that modulates transcription of specific target genes involved in lipid oxidation, lipid transport, lipoprotein assembly, and ketogenesis. During fasting, hepatic PPARA acts as a nutrient sensor and responds to the influx of lipid by upregulating target genes associated with lipid catabolism and ketone body (KB) synthesis to ensure energy availability for extrahepatic tissues. Studies in Ppara-null mice (Ppara−/−) confirmed a critical role for PPARA during prolonged fasting and starvation. These mice experience hepatic lipid accumulation that manifests as pronounced steatosis (1Abdelmegeed M.A. Moon K.H. Hardwick J.P. Gonzalez F.J. Song B.J. Role of peroxisome proliferator-activated receptor-α in fasting-mediated oxidative stress.Free Radic. Biol. Med. 2009; 47: 767-778Crossref PubMed Scopus (59) Google Scholar, 2Leone T.C. Weinheimer C.J. Kelly D.P. A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders.Proc. Natl. Acad. Sci. USA. 1999; 96: 7473-7478Crossref PubMed Scopus (819) Google Scholar, 3Kersten S. Seydoux J. Peters J.M. Gonzalez F.J. Desvergne B. Wahli W. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting.J. Clin. Invest. 1999; 103: 1489-1498Crossref PubMed Scopus (1360) Google Scholar). Fasted Ppara−/− mice also develop hypoketonemia, hypoglycemia, and hypothermia. Hepatic PPARA deficiency is thus a major contributing factor to the observed phenotype. Because PPARA is highly expressed in the liver, the majority of studies have focused on hepatic PPARA action. Nevertheless, PPARA is expressed in most oxidative tissues, including heart, muscle, and kidney, as well as brown adipose tissue (BAT), and activation of extrahepatic PPARA may contribute significantly to lipid homeostasis in response to prolonged fasting. Fasting causes a decrease in blood glucose (GLU) levels and triggers glucagon release from the pancreas. Glucagon elicits a wide range of metabolic alterations, primarily within the liver, to restore energy homeostasis. Hepatic glycogenolysis mobilizes GLU from glycogen stores. Gluconeogenesis also generates GLU from noncarbohydrate sources, including lactate and glycerol (GLY). Prolonged fasting initiates a gradual shift from utilizing carbohydrates and lipids in the fed state to predominantly FAs as GLU stores become exhausted. The shift to lipids as a primary energy source is dependent on the mobilization of FFAs from adipose tissue and circulating lipoproteins. FFAs released from adipose tissue are transported as NEFAs bound to serum albumin. Esterified FAs are transported within circulating lipoproteins. FA uptake by tissues primarily occurs through LPL- or CD36-mediated pathways. LPL hydrolyzes triglyceride (TG)-containing lipoproteins, whereas CD36 acts as a FA translocase to transfer albumin-bound FAs into tissues. Fasting-induced FA influx into oxidative tissues such as the liver, muscle, and heart subsequently activates PPARA, stimulating target gene activation and lipid catabolism. A growing body of evidence indicates that fasting and caloric restriction (CR) imbue many beneficial outcomes, including reduced fat mass, increased insulin sensitivity, reduced cancer prevalence, delayed neurodegeneration, increased longevity, and improved overall health (4Longo V.D. Mattson M.P. Fasting: molecular mechanisms and clinical applications.Cell Metab. 2014; 19: 181-192Abstract Full Text Full Text PDF PubMed Scopus (745) Google Scholar). Fasting causes FA uptake into many PPARA-expressing tissues. Therefore, it is reasonable to assume that PPARA action in extrahepatic tissues significantly contributes to systemic lipid homeostasis during food deprivation. Understanding the underlying mechanisms that drive these metabolic alterations will aid in the development of novel therapeutics that mimic the beneficial effects of fasting or CR regimens. Moreover, hepatic PPARA expression and activity are suppressed in many disease states that cause lipid accumulation within the liver, including nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hepatitis C infections (5Francque S. Verrijken A. Caron S. Prawitt J. Paumelle R. Derudas B. Lefebvre P. Taskinen M.R. Van Hul W. Mertens I. gene expression with and response in with Full Text Full Text PDF PubMed Scopus Google Scholar, W. J. S. A. A. in nonalcoholic fatty liver disease and after Metab. Full Text Full Text PDF PubMed Scopus Google Scholar, S. P. expression of the peroxisome proliferator-activated receptor α during hepatitis C Full Text Full Text PDF PubMed Scopus Google Scholar). and also elevated total and FAs and FFAs in suggesting that PPARA in these in circulating FAs extrahepatic PPARA J. J. serum fatty acid levels and nonalcoholic fatty liver a 2014; PubMed Scopus Google Scholar, total and fatty in Full Text PDF PubMed Scopus Google Scholar). PPARA expression is in the liver, and fasting studies have focused on PPARA action within is in extrahepatic tissues or the overall of extrahepatic PPARA activation to systemic lipid studies have that PPARA expression levels within oxidative liver, heart, kidney, and PPARA is important in tissues, the liver S. R. The role and of the peroxisome receptor α in PubMed Scopus Google Scholar, R. D.P. and peroxisome tissue but to Biol. PubMed Scopus Google Scholar). In studies have that expression levels in tissues are mice and S. R. The role and of the peroxisome receptor α in PubMed Scopus Google Scholar). The development of Ppara-null mice it to the of extrahepatic tissues to systemic lipid homeostasis. This the that extrahepatic PPARA plays a role during metabolic response to fasting and that PPARA activity in tissues can when liver PPARA is WT and Ppara−/− mice in were J. Gonzalez F.J. of the α of the peroxisome proliferator-activated receptor gene in mice in of the effects of peroxisome Biol. PubMed Scopus Google Scholar). and hepatocyte-specific Ppara-null (PparaΔHep) mice were as J. A. Gonzalez F.J. PPARA expression from J. PubMed Scopus Google Scholar). of and mice were in all response the mouse WT and from the mice were to and from were on the and of A was to mouse for were from or mice. were in Ppara−/− or mice with a This that the of all the mice are into the were on a fasting food was for 24 after the of the and the the for total body fat and were mouse on mice were a to a with to a of were by and tissue were for was by of the mice were in a and and food and mouse studies were in with by the and liver tissue was in for 24 and in were for liver tissue was into a and with to a of in were by was a with both and and FAs were in liver tissue after acid In were and of liver tissue was in of in and of in was by a and for The were for The was to a and in a The was in of in and for of was to were for and of was into the for as for were as of was to of mouse were for and of was for The were for and of was to were in a The was by of and for The were with of and for and was into the were and for with factor of was to response through versus with a of for FA were on a were with to with the for to and to with for total The was with a of source and were and and were and The in of was for the was were and can in was on a with and on of were with to with the for to for The was with a The source and was The was in was were and was from mice and to Serum Serum for total total and NEFAs was Serum and levels were as by the GLU levels were a blood GLU serum of serum was by the as and The were for and to for The was for and the was and and the was in by with were by a the and both A and and was A to A to A to A to A to A to with for indicates was was was the as was to and PparaΔHep mice were of the or as a to adipose mice were by and blood was from the a of FAs and were by and as of tissue was in a and was and a of was with and for with were for gene and to and from were to were and to for of J. J. J. R. for and in the PubMed Scopus Google Scholar). are or expression the A model for in PubMed Scopus Google Scholar). can in liver tissue was and for lipid and was a the was as a was to and the in were for a and of and heart, and muscle were in a and were in a total lipase activity was a lipase activity the and to total to the has confirmed for lipase as hepatic lipase and lipase lipase activity also has were a are expressed as the was by or with A of was considered and is indicated in were for the To the of hepatocyte-specific to the fasting and Ppara−/− mice were fed or fasted for 24 for all genotypes in response to fasting of fed mice revealed that of in significantly body fat when compared with or PparaΔHep mice and that the in response to fasting of or fat within Ppara−/− mice also fasting-induced the fasted liver for Ppara−/− mice were or PparaΔHep mice, the liver body all were liver a in fasted Ppara−/− mice, of lipid accumulation S. Seydoux J. Peters J.M. Gonzalez F.J. Desvergne B. Wahli W. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting.J. Clin. Invest. 1999; 103: 1489-1498Crossref PubMed Scopus (1360) Google Scholar). of liver for lipid accumulation in the mouse and was confirmed for in all in response to fasting. levels in Ppara−/− mice were elevated mice and the PparaΔHep mice. staining was to tissue and in fasted Ppara−/− mice were of accumulation was also observed in PparaΔHep mice, but to a staining of was to for lipids and staining confirmed lipid accumulation in fasted Ppara−/− and PparaΔHep mice. WT mice also a in hepatic lipid accumulation when compared with but levels were significantly mouse The accumulation of lipids within the of hepatocyte-specific Ppara-null mice evidence that extrahepatic PPARA significantly contributes to systemic lipid homeostasis in response to FA in was by the accumulation of FAs and and long-chain FAs and and and and PPARA expression in extrahepatic tissues against accumulation of many and and and were significantly in PparaΔHep Ppara−/− mice. revealed that hepatic and extrahepatic PPARA activity on accumulation of and FA and were elevated in WT mice but in both mouse whereas and increased in all after fasting. Serum were to the of extrahepatic PPARA activity on systemic lipid homeostasis. Hepatic steatosis liver and causes liver that is in serum and increased significantly in both mouse after fasting levels were in fasted PparaΔHep Ppara−/− mice, that liver was as Serum was elevated in PparaΔHep mice but by fasting mice were after a 24 was in fasted Ppara−/− mice by PparaΔHep Because PPARA acts as a major regulator of in the liver, total were also Serum increased in all genotypes after response was diminished in both mouse models. levels were and elevated in all genotypes Fasting NEFAs were in Ppara−/− mice when compared with mice, but was when to PparaΔHep mice, phenotype. levels were increased by fasting in and PparaΔHep mice when compared with and in Ppara−/− mice levels in fed were levels were and PparaΔHep mice and by fasting. levels were significantly by fasting in Ppara−/− mice Serum FFAs were in fasted mice by FA were elevated in the serum of Ppara−/− and PparaΔHep mice after fasting and when compared with WT of and were in and other FAs were by fasting or In the levels of were or FAs The release of FFAs from fat stores was to the release of Serum was by levels were elevated in fasted Ppara−/− mice when compared with in PparaΔHep mice were significantly WT or Ppara−/− mice, phenotype. In were also to adipose FA and as well as by tissues, the Serum and response to was to fasted These that extrahepatic PPARA activity serum lipid in fasted PparaΔHep mice. These the of adipose mobilization or increased FA by extrahepatic tissues. the expression of genes involved in FA metabolism were in extrahepatic tissues, and total lipase activity was to FA PPARA target gene lipid and were to that lipid accumulation and PPARA target gene expression associated with FAO and and was dependent on hepatocyte-specific PPARA activation genes that are or to lipid homeostasis including and and are involved in and acid These were in fasted and PparaΔHep mice but Ppara−/− mice. is associated with and fasting in of in Ppara−/− mice. The by and and including to fasting and in PparaΔHep mice. expression was in Ppara−/− mice and after fasting. of was by or in hepatic and decrease in serum in Ppara−/− mice that may genes involved in and and lipid and were These were by fasting or to the Hepatic FAO associated was impaired in both Ppara−/− and PparaΔHep mice. accumulation is to oxidative and R. A. oxidation in the of Radic. Biol. Med. PubMed Scopus Google Scholar). response genes α and were elevated in Ppara−/− mice Moreover, and confirmed in and in the of Ppara−/− after a 24 expressed genes were the pronounced in that extrahepatic tissues may a role in lipid The liver is considered the primary of lipid but many extrahepatic tissues have oxidative expression was in extrahepatic tissues to whether a in FAO may protect against by systemic lipid factor and were in heart, liver, and muscle from fed and fasted and PparaΔHep mice Fasting-induced of all genes in the of WT mice the hepatic FAO deficiency in PparaΔHep and Ppara−/− mice. and expression was in fasted as well as PparaΔHep mice. Fasted PparaΔHep mice significantly expression of and in and in heart, and and in muscle when compared with fasted mice. and expression was after fasting in that FAO is impaired in these tissues. expression was elevated in all tissues but in the liver, suggesting mechanisms in other tissues. FAO in heart, and muscle of fasted PparaΔHep mice circulating lipids and protect against hepatic lipid are for the mobilization of FAs from adipose as well as for the uptake of lipoprotein into tissues. To whether lipid mobilization or total lipase activity was in adipose tissue heart, liver, and muscle from fed and fasted mice lipase activity in increased in all genotypes after a 24 that adipose FA release was by This was by of associated with lipase and in and adipose tissues was by fasting or FA mobilization from fat is total lipase activity was elevated by fasting in and PparaΔHep mice was also a but lipase activity in fasted PparaΔHep mice when compared with WT mice, of lipid utilization. hepatic lipase activity increased in both and PparaΔHep mice after fasting lipase activity in Ppara−/− mice was but significantly elevated in fed mice when compared with mice and after a 24 lipase activity increased in all genotypes but response was in Ppara−/− mice. To elevated extrahepatic lipase and levels were in heart and and was increased in fasted PparaΔHep mice and to fasting. lipase expression was also by total lipase activity in heart and muscle of PparaΔHep mice with in gene expression important role for PPARA during response to and in fasted PparaΔHep mice. were fasted for 24 and tissues were for and gene and were in heart and muscle were to and expressed as WT are versus fed of the Studies utilizing Ppara−/− mice PPARA as a regulator of systemic lipid homeostasis in Fasted Ppara−/− mice are to lipids transported to the liver PparaΔHep mice were to hepatic lipid Ppara−/− mice after a 24 Fasting a in gene expression in heart, and muscle, total lipase activity in heart and muscle, and expression of lipase in PparaΔHep mice. These that PPARA is the primary regulator of FAO in extrahepatic tissues and that FAO significantly contributes to systemic lipid utilization. FAO gene lipase and lipase expression oxidative and lipid lipid and the steatosis and observed in Ppara−/− mice. extrahepatic PPARA plays important role in tissues during food and fasting-induced in the of hepatic of FAO within extrahepatic tissues of in the and of and evidence indicates that hepatic PPARA expression and activity are PPARA plays a major role in lipid homeostasis. studies have the role of PPARA during the fasting response with on the liver A. S. A. into the role of PPARα activity in response to PubMed Scopus Google Scholar, A. A. S. PPARα is for fatty acid homeostasis and is against PubMed Scopus Google Scholar). these studies are by including fasting and to in Fasting for are PPARA expression has a in heart, liver, and but muscle R. B. Desvergne B. Wahli W. J. of the peroxisome proliferator-activated receptor α gene is by and a Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, W. receptor expression the to Full Text Full Text PDF PubMed Scopus Google Scholar, J. heart Biol. PubMed Scopus Google Scholar). the to a fasting is by the that expression is for tissue W. receptor expression the to Full Text Full Text PDF PubMed Scopus Google Scholar). expression in and liver are by significantly the The of on PPARA and PPARA activation in extrahepatic tissues and the on lipid oxidation to the role of PPARA in extrahepatic tissues, the of PPARA in lipid catabolism is in in Ppara-null mice A. A. S. PPARα is for fatty acid homeostasis and is against PubMed Scopus Google Scholar, J. A. S. proliferator-activated mice have increased adipose tissue glucose and fat role in liver and PubMed Scopus Google Scholar, P. J. Peters J.M. Gonzalez F.J. B. mice are from insulin PubMed Scopus Google Scholar, J.M. Gonzalez F.J. of acid on body and target gene expression in peroxisome proliferator-activated receptor PubMed Scopus Google Scholar). WT and PparaΔHep mice body fat to into when fasting-induced hepatosteatosis. genotypes was and the of was by fasting, suggesting that adipose tissue to lipid mobilization was The also that in fasted PparaΔHep mice were and to WT mice. Fasting serum levels to decrease in Ppara−/− mice. The in circulating is to a pronounced of hepatic lipids and by impaired in the levels of genes for and were by or fasting. Moreover, the expression of genes associated with FA and were also These that is the accumulation of FA is to studies have revealed that such as and significantly decrease S. of by fatty in primary is by the PubMed Scopus Google Scholar, in and lipid hepatic and Metab. PubMed Scopus Google Scholar). A pronounced of FAs was in fasted Ppara−/− when compared with of synthesis by FA accumulation decrease and serum as well as hepatosteatosis. can also within the and subsequently S. Hepatic and triglyceride PubMed Scopus Google Scholar). indicated that both and were elevated in fasted Ppara−/− mice. The of synthesis by FA accumulation and oxidative a for the observed in serum after fasting. in other serum were PparaΔHep mice serum and when compared with Ppara−/− mice, that lipids in of serum revealed that levels were in both mouse after fasting. These that hepatic PPARA and that the from extrahepatic tissues has a on circulating Fasting initiates the release of FAs from both adipose tissue and circulating lipoproteins, are transported to other tissues. The liver is considered the primary of lipid and PPARA FAO pathways. The revealed elevated lipids in from Ppara−/− and PparaΔHep mice, were and in WT mice, These with that accumulation in from Ppara−/− and PparaΔHep mice A. A. S. PPARα is for fatty acid homeostasis and is against PubMed Scopus Google Scholar). The of the was to the underlying mechanisms for the in these mouse models. PPARA is primarily considered a hepatic nuclear the indicates that extrahepatic PPARA activity may contribute significantly to systemic lipid homeostasis. FAs are primarily by and FAs and are by are in both and A of and was in Ppara−/− and PparaΔHep suggesting that and are significantly PPARA as FA and of The expression of genes were in of fasted mice and in both Ppara−/− and PparaΔHep mice. The of FAO in extrahepatic tissues for the in hepatic lipid These studies that FAO gene expression was elevated in tissues considered of FAO and of heart, and muscle confirmed the response was observed after fasting in and PparaΔHep mice in all extrahepatic tissues but was in Ppara−/− mice. FAO genes were in PparaΔHep mice when compared with WT mice, that FAO gene expression can as a for with lipid load to hepatic PPARA These that FAO is increased in these tissues and that fasting response in extrahepatic tissues is also by hepatic genes were as in Ppara−/− and PparaΔHep mice. These genes are most expressed in studies have focused on PPARA within other hepatic such as or important role in response and disease and were in fasted and PparaΔHep mice, but Ppara−/− mice. is a and expression was to decrease lipid suggesting that it may contribute to the levels in PparaΔHep mice A. and of involved in the metabolism of acid in Metab. PubMed Scopus Google Scholar, W. action of and from on hepatic and and in PubMed Scopus Google Scholar, S. of in in 2014; PubMed Scopus Google Scholar). is important in acid and expression suggesting that PPARA may important and role in acid was significantly in response to fasting in Ppara−/− mice. A that is in and may as J. J. W. R. is in and associated with Clin. PubMed Scopus Google Scholar). The including plays important role in of cellular studies have effects in the liver, and expression is considered of liver A. R. expression and lipid in the 2014; PubMed Scopus Google Scholar, A. J. J. B. role by in fatty liver in J. Full Text Full Text PDF PubMed Scopus Google Scholar). was to a novel insulin that protects against by and FAO glucose metabolism by both and Biol. PubMed Scopus Google Scholar, protects against hepatic steatosis by both and stimulating fatty acid Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). and expression were suppressed in fasted and PparaΔHep mice, whereas expression increased in Ppara−/− mice. The of these genes during fasting response is but the of genes within novel of hepatic response and The that total lipase activity in oxidative extrahepatic heart and elevated in fasted PparaΔHep mice when compared with Ppara−/− mice and to WT mice, that PPARA expression plays important role in lipid mobilization and in these tissues. Moreover, total lipase activity in fasted PparaΔHep mice was in mice, lipid utilization. Studies have that LPL activity in after a 24 and may the observed in total lipase activity S. S. lipase activity is for lipid 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, of lipoprotein lipase in adipose and muscle tissues during J. Google Scholar). was a in total lipase activity in of all lipase activity was with the that adipose PPARA FA mobilization from adipose stores. The of fasting on the expression of adipose were in and expression was in response to fasting in all adipose that occurs of This is by a that PPARA activation a on the in Ppara−/− mice W. P. P. S. The peroxisome proliferator-activated receptor α is for adipose tissue in Metab. PubMed Scopus Google Scholar). is and and but all levels in total lipase Therefore, levels of serum FFAs and in PparaΔHep mice after fasting, and in response to is most to the uptake and of lipids within tissues. The in FAO gene expression and total lipase activity in oxidative tissues such as heart, muscle, and evidence that metabolism of lipid by extrahepatic tissues can protect against hepatic PPARA expression is in many oxidative tissues, including heart, and PPARA activation is highly dependent on and it is that as a PPARA of energy metabolism by long-chain fatty 2014; PubMed Scopus Google Scholar). During fasting, FAs are and circulating levels This that serum are significantly elevated in Ppara-null mice and that Ppara-null mice phenotype. The in PPARA target gene expression may to circulating in the of in these mice. Moreover, FAs released through also as PPARA M.A. B. J. by LPL activates through of fatty Full Text Full Text PDF PubMed Scopus Google Scholar). The in lipase contribute to elevated PPARA availability in tissues of mice to PPARA activation and as well as target gene is that other nuclear contribute to gene expression and lipid metabolism in the of hepatic PPARA, receptor α is a nuclear receptor expressed levels in tissues that FAO as energy is to as receptor have to but studies have that it plays a role in cellular by contributing to oxidative is to the of PPARA and other nuclear during fasting response in hepatic and tissues. In evidence that extrahepatic PPARA activity significantly contributes to systemic response to prolonged fasting. The that the of FAO in tissues can a role when hepatic PPARA is diminished and circulating lipids are FAO in tissues may have important clinical implications in with associated with impaired hepatic PPARA function, such as and mice were by the of with also as brown adipose tissue caloric restriction and adipose tissue FA oxidation factor glucose adipose tissue ketone body long-chain FA lipid FA nonalcoholic steatohepatitis nonalcoholic fatty liver disease PPARα triglyceride